Endoparasitic depsipeptides

ABSTRACT

The present invention provides cyclic depsipeptides of Formula (1), stereoisomers thereof, and veterinary acceptable salts thereof 
                         
wherein each of R 1 , R 2 , R 3 , R 4 , L 1 , and L 2 , are as defined herein. The present invention also contemplates compositions and methods of treatment as an endoparasiticide with a Formula (1) compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 16/652,136filed Mar. 30, 2020, now allowed; which is a US National Stage entry ofInternational Application No. PCT/US2018/062749, filed Nov. 28, 2018,which claims the benefit of U.S. Provisional Application No. 62/591,942,filed Nov. 29, 2017.

FIELD OF THE INVENTION

The present invention is directed to new endoparasitic depsipeptidecompounds with improved activity against endoparasites. The invention isalso directed to compositions comprising the compounds, methods and usesof the compounds for eradicating, controlling, treating and preventing aparasite infestation and/or infection in animals. The compounds of theinvention may be administered to animals, particularly non-humananimals, to prevent or treat parasitic infections.

BACKGROUND

Animals, such as non-human mammals, for example, companion animals andlivestock, are often susceptible to parasite infestations. Theseparasites may be endoparasites including for example, helminthiasiswhich is most frequently caused by a group of parasitic worms describedas nematodes or roundworms. These parasites cause severe economic lossesin pigs, sheep, horses, and cattle as well as affecting companionanimals (e.g. cats and dogs). Other parasites include those which occurin the gastrointestinal tract of animals and humans include Ancylostoma,Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara,Toxascaris, Trichuris, Enterobius and parasites which are found in theblood or other tissues and organs such as filarial worms and the extraintestinal stages of Strongyloides, Toxocara and Trichinella.

One type of endoparasite which seriously harms animals is Dirofilariaimmitis, also known as heartworm. Other filarial endoparasites includeDirofilaria repens and Dirofilaria honkongensis, which can also infecthumans. The most common hosts are dogs and cats but other mammals suchas ferrets and raccoons may also be infected. Heartworms go throughseveral life stages before they become adults infecting the pulmonaryartery of the host mammal. The worms require the mosquito as anintermediate host to complete their life cycle. The period between theinitial infection when the dog is bitten by a mosquito and thematuration of the worms into adults living in the heart and pulmonaryarteries is six to seven months in dogs and is known as the “prepatentperiod”. L3 larvae migrate during blood feeding of the mosquito to thetip of the mosquito's mouth parts (labium), leave the mosquito and aredeposited on the skin of the dog where they then migrate through thebite wound into the host. Most L3 larvae molt to fourth-stage larvae(L4s) in canine subcutaneous tissues within 1-3 days after infection.Then, they migrate to the muscles of the chest and abdomen, and 45 to 60days after infection, molt to the fifth stage (LS, immature adult).Between 75 and 120 days after infection, these immature heartworms thenenter the bloodstream and are carried through the heart to reside in thepulmonary artery. Around seven months after infection, Dirofilariaimmitis adults reach maturity and sexually reproduce in the pulmonaryarteries and right ventricle. Adult males are around 15 cm in length,and females are around 25 cm in length and their normal life span asadults is calculated to be about 5 years. Heartworm infection is asevere and life-threatening disease. Canine heartworm infection ispreventable and prophylaxis treatment is a priority in heartworm endemicareas. Treatment of mature heartworm infection with an adulticide (e.g.melarsomine dihydrochloride) is costly and can cause serious adverseside effects, thus prevention by monthly administration of drugs thatinterrupt larvae development is widely used. The goal of marketedheartworm preventive therapies in dogs is to prevent the development ofthe parasite to adult heartworms by interrupting the Dirofilaria immitislife cycle post-infection. The macrocyclic lactones (MLs, e.g.ivermectin, eprinomectin, milbemycin ox1me, moxidectin, and selamectin)are the most commonly used chemoprophylaxis agents and are administeredat monthly or six-month intervals. These drugs have been effectiveagainst Dirofilaria immitis infective third-stage larvae (L3) depositedby the mosquito as well as maturing fourth-stage larvae (L4). Whenadministered monthly, MLs kill L3 and L4 larvae acquired within theprevious 30 days, and thus prevent disease caused by adult worms. MLscan also be used monthly in infected dogs to suppress reproduction inadult worms and remove microfilariae, thereby reducing transmission andgradually causing the attrition of adult worms (Vet. Parasitol. 2005,133(2-3), 197-206).

In recent years, an increased number of lack of efficacy cases have beenreported, in which dogs develop mature heartworm infections despitereceiving monthly prophylactic doses of macrocyclic lactone drugs. Forexample, Atkins et al., (Vet. Parasitol. 206 (2014) 106-113) recentlyreported that an increasing number of cases of dogs that testedheartworm antigen positive while receiving heartworm preventivemedication which suggests that some populations of Dirofilaria immitishave developed selectional resistance to heartworm preventives (AmericanHeartworm Society, 2010. Heartworm Preventive Resistance. Is itPossible, vol. 37. Bulletin of the American Heartworm Society, pp. 5).Thus, there is an ongoing need to develop new anthelmintic agents withimproved activity against Dirofilaria immitis and other endoparasites.Various parasiticides exist in the art for treating endoparasitesinfections in animals. In addition to the macrocyclic lactones, cyclicdepsipeptides with antiparasitic activity are known. PF1022A, a24-membered cyclooctadepsipeptide isolated from the fungus Myceliasterilia by Sasaki et al (see J Antibiotics 45: 692-697 (1992)), hasbeen found to exhibit broad anthelmintic activity against a variety ofendoparasites in vivo with low toxicity These compounds are described,for example, in U.S. Pat. Nos. 5,514,773; 5,747,448; 5,646,244;5,874,530; among others, which are incorporated herein by reference.Emodepside is a semi synthetic analog of PF1022A containing a morpholinegroup at the para position of the aryl ring in the phenyl lactategroups. Emodepside is a potent anthelmintic used in combination withpraziquantel in the product Profender® for the treatment of parasiticworms in cats and dogs. However, the antiparasitic activity of PF 1022Aand emodepside is not satisfactory for the treatment of certainparasites, especially for the control of Dirofilaria immitis in mammalsto prevent the establishment of heartworm disease. Thus, there is a needin the art for more effective antiparasitic agents for treatment andprotection of animals, e.g. mammals, fish and birds against parasites,in particular internal parasites including nematodes and filarial wormssuch as heartworm.

SUMMARY OF THE INVENTION

The invention provides novel and inventive cyclic depsipeptide compoundswith selective anthelmintic activity against L3 and L4 stagedendoparasites. In addition, the invention provides compositionscomprising the depsipeptide compounds and methods and uses for thetreatment and prevention of parasitic infection and possibly infestationof animals using the compounds. In one aspect, the present inventionprovides cyclic depsipeptide Formula (1) compounds, shown below:

wherein

L₁ and L₂ are each individually and separately C₁-C₄alkylheteroaryl andC₁-C₄alkylheterocycle, wherein the heteroaryl moiety is a 5- or 6-membermonocyclic aromatic ring or a 8- to 11-member fused aromatic ring eachcontaining at least one heteroatom selected from N, O, and S; and theheterocycle moiety is a 4- to 6-member monocyclic saturated or partiallysaturated ring or a 8- to 11-member fused saturated or partiallysaturated ring, and wherein the heteroaryl and heterocycle moiety areN-linked to the alkyl;

and wherein the L₁ and L₂ alkyl moiety of the alkylheteroaryl andalkylheterocycle is optionally substituted with at least one substituentselected from the group consisting of halo, C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₄alkoxy, C₃-C₆cycloalkyl, and nitro; or at least two alkylsubstitutions of each of the L₁ and L₂ alkyl moieties can join togetherto each form a C₃-C₆cycloalkyl ring;

or L₁ is absent;

and wherein the L₁ and L₂ heteroaryl and heterocycle moiety are eachindependently and separately optionally substituted with at least onesubstituent selected from C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,wherein the alkyl, alkenyl and alkynyl groups are independently andseparately optionally substituted with at least one substituent selectedfrom hydroxyl, cyano, C₃-C₆ cycloalkyl, —NR^(a)R^(b), C₁-C₄alkoxy,morpholine, and phenyl;

or halo, cyano, nitro, —NR^(a)R^(b), oxo, hydroxyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, saturated or partially saturatedC₃-C₆cycloalkyl optionally substituted with at least one substituentselected from C₁-C₃alkyl, amino, cyano, halo, and C₁-C₃alkoxy;

or phenyl optionally substituted with at least one substituent selectedfrom halo, cyano, C₁-C₄alkyl, and C₁-C₄alkoxy;

or a saturated or partially saturated 4- to 6-membered heterocycle ringcontaining at least one heteroatom selected from N, O, and S and furtheroptionally substituted with C₁-C₄alkyl;

or a 5- to 6-membered heteroaryl ring containing at least one heteroatomselected from N, O, and S and further optionally substituted with atleast one substituent selected from halo, cyano, C₁-C₄alkyl,C₁-C₄haloalkyl and C₁-C₄alkoxy;

or —C(O)R, —COR, —C(O)OR, —CS(O)_(p)R^(a), —C(O)NR^(a)R^(b), —SR,—C(O)X, —OX, —S(O)_(p)R, —S(O)_(p)X, —CNR^(a)C(O)R, CNR^(a)C(O)OR,—CNR^(a)R^(b), —CNH₂(N)OH, —NR^(a)C(O)R, —NR^(a)C(O)OR,—NR^(a)S(O)_(p)R, —NR^(a)C(O)NR^(a)R^(b),—OR^(e)—OR^(e)NR^(a)C(O)OR^(e), —OR^(e)C(O)OH;

R is C₁-C₆alkyl, amino, C₁-C₆haloalkyl, phenyl optionally substitutedwith at least one substituent selected from C₁-C₃alkoxy, cyano, halo,C₁-C₃alkyl, and C₁-C₃haloalkyl;

R¹, R², R³, and R⁴ are each separately and independently H andC₁-C₆alkyl;

R^(a) and R^(b) are each separately H, C₁-C₆alkyl, C₁-C₃haloalkyl,C₃-C₆cycloalkyl, and phenyl optionally substituted with halo, amino, andC₁-C₃haloalkyl;

R^(e) is C₁-C₆alkyl optionally substituted with halo, amino,C₃-C₆cycloalky, and C₁-C₄alkoxy;

X is an N-linked 4- to 6-membered saturated or partially saturatedheterocyclic ring optionally containing at least one additionalheteroatom selected from N, O, and S; or X is a 5- to 6-memberedheteroaryl ring containing at least one heteroatom selected from N, O,and S; or X is phenyl optionally substituted with at least onesubstituent selected from C₁-C₄haloalkyl, halo, amino, cyano,C₁-C₄alkyl, and C₁-C₄alkoxy; or X is a saturated or partially saturatedC₃-C₆ cycloalkyl ring; and

p is the integer 0, 1, or 2, stereoisomers thereof, and veterinaryacceptable salts thereof.

In one aspect of the invention, L₁ and L₂ are each separatelyC₁alkylheteroaryl (C₁heteroaryl) and C₁alkylheterocycle (C₁heterocycle).In another aspect of the invention, L₁ and L₂ are C₁heteroaryl. In oneaspect of the invention, L₁ and L₂ are each C₁heteroaryl and are bothattached to the para-carbon of the phenyl ring. In one aspect of theinvention, L₁ and L₂ are each C₁heteroaryl and L₁ is attached to themeta-carbon of the phenyl ring and L₂ is attached to the para-carbon ofthe phenyl ring. In one aspect of the invention, L₁ and L₂ are eachC₁heteroaryl and L₁ is attached to the ortho-carbon of the phenyl ringand L₂ is attached to the para-carbon of the phenyl ring. In one aspectof the invention, L₁ and L₂ are each C₁heteroaryl and L₁ and L₂ are bothattached to the meta-carbon of the phenyl ring. In yet another aspect ofthe invention, L₁ is absent and L₂ is C₁heteroaryl. In yet anotheraspect of the invention, L₁ is absent and L₂ is C₁heteroaryl attached tothe para-carbon of the phenyl ring. In yet another aspect of theinvention, L₁ is absent and L₂ is C₁heteroaryl attached to themeta-carbon of the phenyl ring. Preferrably, in one aspect, L₁ and L₂are both heteroaryl and are attached to the para-carbon of the phenylring.

In another aspect of the invention, L₁ and L₂ are C₁heterocycle. In oneaspect of the invention, L₁ and L₂ are each C₁heterocycle and L₁ and L₂are both attached to the para-carbon of the phenyl ring. In one aspectof the invention, L₁ and L₂ are each C₁heterocycle and L₁ is attached tothe meta-carbon of the phenyl ring and L₂ is attached to the para-carbonof the phenyl ring. In one aspect of the invention, L₁ and L₂ are eachC₁ heterocycle and L₁ is attached to the ortho-carbon of the phenyl ringand L₂ is attached to the para-carbon of the phenyl ring. In one aspectof the invention, L₁ and L₂ are each C₁heterocycle and L₁ and L₂ areboth attached to the meta-carbon of the phenyl ring. In yet anotheraspect of the invention, L₁ is absent and L₂ is C₁heterocycle. In yetanother aspect of the invention, L₁ is absent and L₂ is C₁heterocycleattached to the para-carbon of the phenyl ring. In yet another aspect ofthe invention, L₁ is absent and L₂ is C₁heterocycle attached to themeta-carbon of the phenyl ring. Preferrably, in one aspect, L₁ and L₂are both heterocycle and are attached to the para-carbon of the phenylring.

In another aspect of the invention, L₁ is C₁heteroaryl and L₂ isC₁heterocycle. In each case, L₁ and L₂ are separately and individuallyattached to the respective para-carbon, meta-carbon, or ortho-carbon onthe phenyl ring with the N atom of the hetero ring.

In one aspect of the invention, the L₁ and L₂ heteroaryls are eachindependently selected from a 5- to 6-member monocyclic ring or a 8- to11-member fused ring each containing at least one heteroatom selectedfrom N, O, and S. In another aspect of the invention the L₁ and L₂heteroaryls include pyrrole, pyrazole, imidazole, isoxazole, oxazole,isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole,pyridine, pyridazine, pyrimidine, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, indole, benzimidazole, indazole,benzotriazole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine,3,4-dihydro-2H-benzo[b][1,4]oxazine, 1H-benzo[d]triazole,pyridine-2(1H)-one, 2,3-dihydroquinoline,3,4-dihydro-2H-benzo[b][1,4]oxazine, 1H-pyrrolo[2,3-b]pyridine,1H-pyrrolo[2,3-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, pyridine,pyrimidine, and the like. In yet another aspect of the invention, the L₁and L₂ heteroaryls include pyrrole, pyrazole, imidazole, thiazole,triazole, tetrazole, pyridine, and pyrimidine. In yet another aspect ofthe invention, the L₁ and L₂ heteroaryls include pyrazole, imidazole,and thiazole. In yet another aspect of the invention, the L₁ and L₂heteroaryls are pyrazole and imidazole. In yet another aspect of theinvention, the L₁ and L₂ heteroaryls are pyrazole. In yet another aspectof the invention, the L₁ and L₂ heteroaryls are imidazole. The L₁ and L₂heteroaryls are optionally substituted as described herein.

In another aspect of the invention, the L₁ and L₂ heterocycles are eachindependently selected from a 4-, 5-, or 6-member monocyclic saturatedor partially saturated ring or a 8- to 11-member fused saturated orpartially saturated ring, each containing at least one heteroatomselected from N, O, and S. In yet another aspect of the invention, theL₁ and L₂ heterocycles include azetidine, pyrrolidine, piperidine,morpholine, piperazine, azathiane, imidazolidine, oxazolidine,tetrahydropyran, 1,2,3,4-tetrahydropyridine, 1,2,5,6-tetrahydropyridine,thiomorpholine, 2,4,5,6-tetrahydrocyclopenta[c]pyrrole,1,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole,2,3,3a,4,5,6-hexahydrocyclo-pental[c]pyrazole,1,3a,4,5,7,7a-hexahydropyrano[3,4-c]pyrazole, 1,3-oxazinane, and thelike. In yet another aspect of the invention, the L₁ and L₂ heterocyclesinclude pyrrolidine, piperidine, morpholine, piperazine, azathiane, andoxazolidine. In yet another aspect of the invention, the L₁ and L₂heterocycles include pyrrolidine, piperidine, morpholine, andpiperazine. In yet another aspect of the invention, the L₁ and L₂heterocycles include pyrrolidine, piperidine, and morpholine. In yetanother aspect of the invention, the L₁ and L₂ heterocycles arepyrrolidine. In yet another aspect of the invention, the L₁ and L₂heterocycles are piperidine. In yet another aspect of the invention, theL₁ and L₂ heterocycles are morpholine. The L₁ and L₂ heterocycles areoptionally substituted as described herein.

In yet another aspect of the invention, R¹, R², R³, and R⁴ are eachseparately and independently H, methyl, ethyl, propyl, isopropyl, butyl,and isobutyl. In yet another aspect of the invention, R¹, R², R³, and R⁴are each separately and independently methyl, ethyl, propyl, andisopropyl. In yet another aspect of the invention, R¹, R², R³, and R⁴are each separately and independently methyl, ethyl, and isopropyl. Inyet another aspect of the invention, R¹, R², R³, and R⁴ are isopropyl.

In yet another aspect of the invention, the L₁ and L₂ heteroaryl andheterocycle moiety are each independently and separately optionallysubstituted with at least one substituent selected from C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, wherein the alkyl, alkenyl and alkynylgroups are independently and separately optionally substituted withhydroxyl, bromo, fluoro, chloro, iodo, amino, cyano, cyclopropyl, andphenyl; halo, cyano, nitro, amino, hydroxyl, —CHF₂, —CF₃, —CH₂F,—CH₂CHF₂, —CH₂CH₂F, —CH₂CF₃; cyclopropyl, cyclobutyl, and cyclopentyl,each optionally substituted with at least one methyl, ethyl, halo,methoxy, ethoxy, amino, and cyano; cyclopentene, cyclohexene, oxetane,tetrahydro-2H-pyran, morpholine; furan, thiazole, triazolyl, thiophenyl,pyrrole, pyridine, pyrimidine, and pyrazine each optionally substitutedwith at least one substituent selected from methyl, methoxy, and ethoxy;phenyl optionally substituted with halo, methoxy, and methyl; methoxy,ethoxy, isopropoxy, isobutoxy, oxo, —C(O)N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃,—C(O)CH₃, —C(O)CH₂CH₃, —C(O)C(CH₃)₃, —C(O)CH(CH₃)₂, —C(O)OCH₂CH₃,—C(O)OC(CH₃)₃, —C(O)OC(CH₃)₂, —C(O)N-cyclopropyl, —CH₂NHC(O)OC(CH₃)₃,—CH₂NHC(O)CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —NHC(O)OCH₃,—NHC(O)CH₃, —NHS(O)₂CH₃, —NHC(O)OC(CH₃)₃, —NHC(O)OCH₂CF₃,—NHC(O)NH—C(CH₃)₃, and —NHC(O)NH-phenyl optionally substituted with—CF₃; —C(O)-azetidine, —C(O)-pyrrolidine, —C(O)-piperidine,—C(O)-morpholine, —S(O)₂CH₃, —S(O)₂NH₂, —SC(CH₃)₂, —S(O)₂-azetidine,—S(O)₂-pyrrolidine, —S(O)₂-piperidine, —S(O)₂-morpholine, —OCHF₂,—OCH₂F, —OCF₃, —OCH₂CF₃, —OCH₂-cyclopropyl, —O-cyclopropyl,—O-cyclobutyl, —O-cyclopentyl, —O-oxetane, —OCH₂OCH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂C(O)OH, —OCH₂CH₂NH₂, —OCH₂CH₂NC(O)OC(CH₃)₃; O-thiazole,O-pyridine, each optionally substituted with methyl, halo, and methoxy.

In yet another aspect of the invention, the L₁ and L₂ heteroaryl andheterocycle moiety are each independently and separately optionallysubstituted with at least one substituent selected from C₁-C₆alkyloptionally substituted with hydroxyl, bromo, fluoro, chloro, iodo,amino, cyano, cyclopropyl, and phenyl; halo, cyano, nitro, amino,hydroxyl, —CHF₂, —CF₃, —CH₂F; cyclopropyl, cyclobutyl, and cyclopentyl,each optionally substituted with at least one methyl, ethyl, halo,methoxy, ethoxy, amino, and cyano; oxetane, morpholine; phenyloptionally substituted with halo, methoxy, and methyl; methoxy, ethoxy,isopropoxy, isobutoxy, oxo, —C(O)N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃,—C(O)CH₃, —C(O)CH₂CH₃, —C(O)C(CH₃)₃, —C(O)CH(CH₃)₂, —C(O)OCH₂CH₃,—C(O)OC(CH₃)₃, —C(O)OC(CH₃)₂, —CH₂NHC(O)CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, —NHC(O)OCH₃, —NHC(O)CH₃, —NHS(O)₂CH₃,—NHC(O)OC(CH₃)₃, —NHC(O)NH—C(CH₃)₃, —S(O)₂CH₃, —S(O)₂NH₂, —SC(CH₃)₂,—OCHF₂, —OCH₂F, —OCF₃, —OCH₂CF₃, —OCH₂OCH₃, OCH₂CH₂OCH₃,—OCH₂-cyclopropyl, —O-cyclopropyl, —O-cyclobutyl, —O-cyclopentyl, and—O-oxetane.

In yet another aspect of the invention, the L₁ and L₂ heteroaryl andheterocycle moiety are each independently and separately optionallysubstituted with at least one substituent selected from C₁-C₆alkyloptionally substituted with hydroxyl, bromo, fluoro, chloro, iodo, andcyclopropyl; halo, methoxy, ethoxy, isopropoxy, isobutoxy, hydroxyl,—CHF₂, —CF₃, —CH₂F; cyclopropyl, cyclobutyl, and cyclopentyl, eachoptionally substituted with at least one methyl, halo, methoxy, andethoxy; oxetane; morpholine; —C(O)CH₃, —C(O)CH₂CH₃, —C(O)C(CH₃)₃,—C(O)CH(CH₃)₂, —CH₂NHC(O)CH₃, —S(O)₂CH₃, —SC(CH₃)₂, —OCHF₂, —OCH₂F,—OCF₃, —OCH₂CF₃, —OCH₂OCH₃, OCH₂CH₂OCH₃, —OCH₂-cyclopropyl,—O-cyclopropyl, —O-cyclobutyl, —O-cyclopentyl, and —O-oxetane.

In yet another aspect of the invention, the L₁ and L₂ heteroaryl andheterocycle moiety are each independently and separately optionallysubstituted with at least one substituent selected from methyl, ethyl,propyl, isopropyl, t-butyl, sec-butyl, amino, —CH₂F, —CHF₂, —CF₃;—CH₂OH, —CH₂CH₂OH, —CH₂CN, cyclopropyl, methoxy, ethoxy, isopropoxy,hydroxyl, cyano, amino, and halo; and wherein the cyclopropyl moiety isoptionally substituted with at least one substituent selected frommethyl, fluoro, chloro, bromo, methoxy, and ethoxy.

In yet another aspect of the invention, the L₁ and L₂ heteroaryl andheterocycle moiety are each independently and separately optionallysubstituted with at least one substituent selected from C₁-C₆alkyl,halo, cyano, C₁-C₆haloalkyl, C₃-C₆cycloalkyl optionally substituted withat least one substituent selected from fluoro, chloro, methyl, andmethoxy; C₁-C₆alkoxy, phenyl optionally substituted with at least onesubstituent selected from halo and methoxy; —C₁-cyclopropyl, andC₂-C₆alkynl optionally substituted with cyclopropyl or phenyl. In yetanother aspect of the invention, the L₁ and L₂ heteroaryl, andheterocycle moiety are each independently and separately optionallysubstituted with at least one substituent selected from methyl, ethyl,propyl, isopropyl, t-butyl, isobutyl, sec-butyl, cyano, bromo, fluoro,chloro, iodo, —CH₂F, —CHF₂, —CF₃; cyclopropyl, cylobutyl, cyclopentyl,each optionally substituted with at least substituent selected fromfluoro, chloro, methyl, and methoxy; methoxy, ethoxy, isopropoxy,isobutoxy; phenyl optionally substituted with at least one substituentselected from halo and methoxy; C₂-C₆alkynl optionally substituted withcyclopropyl or phenyl; pyrrole optionally substituted with at least onesubstituent selected from cyano and methyl.

In yet another aspect of the invention, the L₁ and L₂ heteroaryl andheterocycle moiety are each independently and separately optionallysubstituted with a 10-membered fused partially saturated heterocyclicring containing at least one heteroatom selected from the N, O, and S,and wherein said ring is optionally substituted with oxo.

In yet another aspect of the invention, R^(a) and R^(b) are eachseparately H, methyl, ethyl, propyl, isopropyl, isobutyl, —CH₂F, —CHF₂,—CF₃, —CH₂CHF₂, —CH₂CF₃, cyclopropyl, cyclobutyl; and phenyl optionallysubstituted with fluoro, chloro, amino, and —CF₃.

In yet another aspect of the invention, R^(e) is methyl, ethyl, propyl,isopropyl, butyl and isobutyl, each optionally substituted with fluoro,chloro, amino, cyclopropyl, cyclobutyl, methoxy, ethoxy, and isopropoxy.

In yet another aspect of the invention, X is an N-linked 4- to6-membered heterocyclic ring selected from azetidine, pyrrolidine,piperidine, and morpholine. In yet another aspect of the invention, X isa 5- to 6-membered heteroaryl ring selected from thiazolyl andpyridinyl. In yet another aspect of the invention, X is phenyloptionally substituted with at least one substituent selected from —CF₃,fluoro, chloro, amino, cyano, methyl, ethyl, methoxy, and ethoxy. In yetanother aspect of the invention, X is a saturated or partially saturatedC₃-C₆ cycloalkyl ring selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentane, and cyclohexene.

In yet another aspect of the invention, p is the integer 0. In yetanother aspect, p is the integer 1. In yet another aspect of theinvention, p is the integer 2.

In yet another aspect of the invention, is a compound of Formula (1)that is a Formula (1A) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1A) compound that is aFormula (1A1) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1A1) that is a Formula(1A1-1) or Formula (1A1-2) compound,

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1A1-1) compound,stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, are compounds of Formula (1A1-1)selected from those compounds presented in Table 1a and Table 1b. In yetanother aspect of the invention, are compounds of Formula (1A1-1)selected from those compounds presented in Table 1a. In yet anotheraspect of the invention, are compounds of Formula (1A1-1) selected fromthose compounds presented in Table 1b. In yet another aspect of theinvention are Formula (1A1-1) compounds (example #) selected from thegroup consisting of:((3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone)(1b-14);((3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(4-ethoxypyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone)(1b-21);((3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-(pyrazol-1-ylmethyl)phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone)(1b-23);((3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone)(1b-108);((3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(difluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone)(1b-211);((3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(1-fluorocyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone)(1b-215);((3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(2,2-difluorocyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone)(1b-216); and((3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(2-methylcyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone)(1b-222); stereoisomers thereof, and veterinary acceptable saltsthereof.

In yet another aspect of the invention, is a Formula (1A1-2) compound,stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, are compounds of Formula (1A1-2)selected from those compounds presented in Table 6. In yet anotheraspect of the invention, are compounds of Formula (1A1-1) presented inTable 1 (1a and 1b) and Formula (1A1-2) compounds presented in Table 6.

In yet another aspect of the invention, is a Formula (1) compound thatis a Formula (1A1-3) compound, stereoisomers thereof, and veterinaryacceptable salts thereof.

In yet another aspect of the invention, are compounds of Formula (1A1-3)selected from those compounds presented in Table 1c. In yet anotheraspect of the invention is the Formula (1A1-3) compound (example #),((3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(1-(1H-pyrazol-1-yl)cyclobutyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone)(1c-1), stereoisomers thereof, and veterinary acceptable salts thereof.

In yet another aspect of the invention, is a Formula (1) compound thatis a Formula (1B) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1B) compound that is aFormula (1B1) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1B1) compound that is aFormula (1B1-1) or Formula (1B1-2) compound,

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1B1-1) compound,stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, are compounds of Formula (1B1-1)selected from those compounds presented in Table 2. In yet anotheraspect of the invention, is a Formula (1B1-2) compound, stereoisomersthereof, and veterinary acceptable salts thereof. In yet another aspectof the invention, are compounds of Formula (1B1-2) selected from thosecompounds presented in Table 8. In yet another aspect of the invention,are compounds of Formula (1B1-1) presented in Table 2 and compounds ofFormula (1B1-2) presented in Table 8.

In yet another aspect of the invention, is a Formula (1) compound thatis a Formula (1C) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1C) compound that is aFormula (1C1) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1C1) compound that is aFormula (1C1-1) compound or Formula (1C1-2) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1C1-1) compound,stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, are compounds of Formula (1C1-1)selected from those compounds presented in Table 3. In yet anotheraspect of the invention, is a Formula (1C1-2) compound, stereoisomersthereof, and veterinary acceptable salts thereof. In yet another aspectof the invention, are compounds of Formula (1C1-2) selected from thosecompounds presented in Table 7.

In yet another aspect of the invention, is a Formula (1) compound thatis a Formula (1D) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1D) compound that is aFormula (1D1) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1D1) compound that is aFormula (1D1-1) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, are compounds of Formula (1D1-1)selected from those compounds presented in Table 4.

In yet another aspect of the invention, is a Formula (1) compound thatis a Formula (1E1) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, are compounds of Formula (1E1) selectedfrom those compounds presented in Table 5.

In yet another aspect of the invention, is a Formula (1) compound thatis a Formula (1F1) compound or Formula (1F2) compound

stereoisomers thereof, and veterinary acceptable salts thereof. In yetanother aspect of the invention, is a Formula (1F1) compound. In yetanother aspect of the invention are compounds of Formula (1F1) selectedfrom those compounds presented in Table 9. In yet another aspect of theinvention, is a Formula (1F2) compound. In yet another aspect of theinvention, are compounds of Formula (1F2) selected from those compoundspresented in Table 10.

In yet another aspect of the invention, are compounds that have aMinimal Effective Dose (MED) against D. immitis microfilaria (DiMF) at avalue of nM and include: 1a-36, 1a-37, 1b-16, 1b-17, 1b-18, 1b-23,1b-32, 1b-66, 1b-86, 1b-96, 1b-104, 1b-115, 1b-146, 1b-160, 1b-166,1b-168, 1b-171, 1b-173, 1b-176, 1b-177, 1b-189, 1b-194, 1b-208, 1b-212,1c-1, 1c-3, 1c-4, 1c-6, 1c-7, 1c-9, 1c-10, 2-1, 2-30, 6-3, 6-9, 6-15,8-9, 9-12, 9-16, 9-32, 9-50, 9-54, 9-55, 10-13, and 10-31; each of whichare respectively named herein. In yet another aspect of the invention,are compounds with a DiMF MED of >1 nM and ≤10 nM and include 1a-1,1a-2, 1a-7, 1a-10, 1a-11, 1a-16, 1a-17, 1a-20, 1a-21, 1a-24, 1a-38,1a-46, 1b-7, 1b-8, 1b-10, 1b-19, 1b-21, 1b-24, 1b-25, 1b-29, 1b-35,1b-46, 1b-52, 1b-62, 1b-70, 1b-89, 1b-94, 1b-95, 1b-103, 1b-105, 1b-108,1b-118, 1b-119, 1b-121, 1b-126, 1b-135, 1b-142, 1b-143, 1b-145, 1b-150,1b-151, 1b-152, 1b-154, 1b-155, 1b-165, 1b-174, 1b-175, 1b-184, 1b-190,1b-197, 1b-201, 1b-203, 1b-205, 1b-207, 1b-211, 1b-213, 1b-215, 1b-216,1b-220, 1b-221, 1c-2, 1c-5, 1c-11, 1c-12, 2-2, 2-7, 2-10, 2-12, 2-18,2-19, 2-22, 2-25, 2-28, 2-29, 2-39, 2-41, 2-44, 2-45, 2-46, 2-47, 2-48,2-51, 2-55, 2-62, 2-65, 2-66, 2-69, 2-74, 2-75, 2-76, 2-77, 2-87, 3-1,3-2, 3-3, 3-8, 3-11, 3-27, 3-36, 3-37, 3-39, 3-41, 4-1, 4-2, 4-14, 5-1,5-2, 6-1, 6-12, 6-16, 6-19, 6-20, 7-3, 7-9, 8-3, 8-7, 8-8, 8-12, 8-13,8-15, 9-1, 9-6, 9-11, 9-21, 9-22, 9-25, 9-28, 9-30, 9-34, 9-41, 9-48,9-49, 9-51, 9-52, 9-53, 9-56, 10-6, 10-17, 10-30, 10-37, and 10-38; eachof which are respectively named herein. In yet another aspect of theinvention, are compounds with a DiMF MED value of >10 and ≤100 nM andinclude: 1a-3, 1a-6, 1a-8, 1a-12, 1a-13, 1a-14, 1a-15, 1a-18, 1a-19,1a-22, 1a-23, 1a-25, 1a-26, 1a-28, 1a-29, 1a-30, 1a-31, 1a-32, 1a-33,1a-35, 1a-39, 1b-4, 1b-5, 1b-12, 1b-13, 1b-15, 1b-20, 1b-22, 1b-31,1b-34, 1b-38, 1b-39, 1b-43, 1b-45, 1b-53, 1b-54, 1b-58, 1b-63, 1b-64,1b-67, 1b-69, 1b-71, 1b-75, 1b-87, 1b-91, 1b-97, 1b-106, 1b-110, 1b-111,1b-112, 1b-113, 1b-116, 1b-117, 1b-120, 1b-124, 1b-127, 1b-128, 1b-129,1b-133, 1b-138, 1b-139, 1b-140, 1b-141, 1b-144, 1b-149, 1b-156, 1b-159,1b-162, 1b-163, 1b-169, 1b-170, 1b-172, 1b-180, 1b-181, 1b-183, 1b-185,1b-186, 1b-187, 1b-188, 1b-191, 1b-195, 1b-198, 1b-199, 1b-206, 1b-209,1b-210, 1b-214, 1b-217, 1b-218, 1b-219, 1b-222, 2-3, 2-5, 2-8, 2-9,2-11, 2-13, 2-14, 2-15, 2-16, 2-17, 2-20, 2-21, 2-23, 2-24, 2-26, 2-27,2-31, 2-32, 2-35, 2-36, 2-38, 2-40, 2-42, 2-43, 2-50, 2-52, 2-54, 2-56,2-57, 2-58, 2-59, 2-60, 2-61, 2-64, 2-67, 2-68, 2-70, 2-71, 2-72, 2-78,2-79, 2-81, 2-82, 2-83, 2-84, 2-85, 2-86, 2-88, 3-10, 3-12, 3-13, 3-18,3-19, 3-20, 3-21, 3-23, 3-24, 3-25, 3-29, 3-38, 3-43, 4-9, 4-15, 4-16,4-17, 5-3, 5-4, 5-6, 6-2, 6-4, 6-5, 6-6, 6-7, 6-8, 6-10, 6-11, 6-14,6-18, 7-1, 7-2, 7-4, 7-7, 7-11, 8-2, 8-4, 8-5, 8-6, 8-10, 8-11, 8-14,9-2, 9-4, 9-5, 9-18, 9-20, 9-27, 9-29, 9-33, 9-35, 9-42, 9-57, 9-58,9-59, 9-61, 9-62, 9-64, 10-2, 10-3, 10-9, 10-10, 10-11, 10-12, 10-14,10-16, 10-18, 10-19, 10-21, 10-22, 10-23, 10-24, 10-25, 10-26, 10-27,10-28, 10-32, 10-33, 10-35, and 10-41; each of which are respectivelynamed herein.

In yet another aspect of the invention, are compounds that have aMinimal Effective Dose (MED) against D. immitis L4 larvae (DiL4) at avalue of 0.1 nM an include compounds 1a-7, 1b-15, 1b-66, 1b-89, 1b-96,1b-115, 1b-119, 1b-154, 1b-166, 1b-171, 1b-176, 1b-177, 1b-211, 1b-216,1c-1, 1c-2, 1c-3, 1c-6, 1c-7, 1c-8, 1c-10, 1c-11, 6-3, 6-9, 6-12, 9-12,9-16, 9-48, and 10-31; each of which are respectively named herein. Inyet another aspect of the invention, are compounds that have an MEDvalue against DiL4 of >0.1 to ≤1 nM and include 1a-1, 1a-11, 1a-12,1a-13, 1a-16, 1a-20, 1a-21, 1a-26, 1a-31, 1a-36, 1a-37, 1b-16, 1b-17,1b-21, 1b-23, 1b-25, 1b-32, 1b-35, 1b-46, 1b-51, 1b-86, 1b-104, 1b-108,1b-112, 1b-113, 1b-118, 1b-126, 1b-129, 1b-150, 1b-151, 1b-160, 1b-165,1b-173, 1b-186, 1b-189, 1b-190, 1b-194, 1b-205, 1b-206, 1b-209, 1b-210,1b-212, 1b-215, 1b-217, 1b-219, 1b-222, 1c-4, 1c-5, 1c-12, 1c-13, 2-1,2-10, 2-22, 2-25, 2-28, 2-41, 2-51, 2-55, 2-62, 2-64, 2-66, 2-69, 2-76,2-77, 3-1, 3-3, 3-18, 3-19, 3-27, 3-36, 3-37, 4-2, 6-15, 7-3, 7-9, 8-3,8-9, 8-12, 8-15, 9-25, 9-26, 9-32, 9-55, 10-13, 10-30, and 10-38; eachof which are respectively named herein. In yet another aspect of theinvention, are compounds that have an MED value against DiL4 of >1 to≤10 nM and include 1a-34, 1a-38, 1a-39, 1b-14, 1b-19, 1b-68, 1b-69,1b-127, 1b-128, 1b-143, 1b-146, 1b-147, 1b-149, 1b-152, 1b-153, 1b-155,1b-168, 1b-172, 1b-174, 1b-175, 1b-178, 1b-181, 1b-184, 1b-187, 1b-197,1b-201, 1b-203, 1b-207, 1b-208, 1b-220, 1b-221, 9-1, 9-22, 9-50, 9-51,9-52, 9-53, 9-54, 9-56, 9-58, 9-61, 9-63, and 10-6; each of which arerespectively named herein.

In yet another aspect of the invention, are compounds of the inventionthat are selectively potent against DiL4 with a DiMF/DiL4 ratio≥10 to<100 and include: 1a-1, 1a-12, 1a-13, 1a-20, 1a-26, 1a-31, 1a-34, 1b-14,1b-35, 1b-46, 1b-69, 1b-89, 1b-96, 1b-108, 1b-113, 1b-126, 1b-127,1b-128, 1b-129, 1b-149, 1b-151, 1b-171, 1b-172, 1b-186, 1b-206, 1b-209,1b-215, 1b-216, 1b-217, 1b-219, 1c-5, 1c-8, 1c-10, 1c-11, 2-41, 2-55,2-69, 3-3, 3-18, 3-19, 4-2, 6-12, 9-16, 9-61, 10-31, and 10-38; each ofwhich are respectively named herein. In yet another aspect of theinvention, are compounds that are selectively potent against DiL4including 1a-1, 1a-12, 1a-13, 1a-20, 1a-26, 1a-31, and 1a-34; each ofwhich are respectively named herein. In yet another aspect of theinvention, are compounds that are selectively potent against DiL4including 1b-14, 1b-35, 1b-46, 1b-69, 1b-89, 1b-96, 1b-108, 1b-113,1b-126, 1b-127, 1b-128, 1b-129, 1b-149, 1b-151, 1b-171, 1b-172, 1b-186,1b-206, 1b-209, 1b-215, 1b-216, 1b-217, and 1b-219; each of which arerespectively named herein. In yet another aspect of the invention, arecompounds that are selectively potent against DiL4 including 1c-5, 1c-8,1c-10, and 1c-11; each of which are respectively named herein. In yetanother aspect of the invention, are compounds that are selectivelypotent against DiL4 including 2-41, 2-55, 2-69, 3-3, 3-18, 3-19, 4-2,6-12, 9-16, 9-61, 10-31, and 10-38; each of which are respectively namedherein. In yet another aspect of the invention, are compounds that areselectively potent against DiL4 with a DiMF/DiL4 ratio≥100 and include:1a-7, 1b-15, 1b-51, 1b-68, 1b-112, 1b-119, 1b-153, 1b-154, 1b-178,1b-210, 1b-222, 1c-2, 1c-3, 1c-11, 1c-13, 2-64, 9-26, 9-48, and 9-63;each of which are respectively named herein. In yet another aspect ofthe invention, are compounds that are selectively potent against DiL4including 1a-7; which is respectively named herein. In yet anotheraspect of the invention, are compounds that are selectively potentagainst DiL4 including: 1b-15, 1b-51, 1b-68, 1b-112, 1b-119, 1b-153,1b-154, 1b-178, 1b-210, and 1b-222; each of which are respectively namedherein. In yet another aspect of the invention, are compounds that areselectively potent against DiL4 including: 1c-2, 1c-3, 1c-11, and 1c-13;each of which are respectively named herein. In yet another aspect ofthe invention, are compounds that are selectively potent against DiL4including: 2-64, 9-26, 9-48, and 9-63; each of which are respectivelynamed herein.

In yet another aspect of the invention, are compounds that had an MED≤1μM against H. contortus L3 larvae including: 1b-18, 1b-23, 1b-66, 1b-89,1b-94, 1b-96, 1b-104, 1b-108, 1b-115, 1b-151, 1b-160, 1b-165, 1b-171,1b-173, 1b-176, 1b-177, 1b-206, 1b-211, 1b-212, 1b-215, 1b-216, 1b-217,1b-219, 1b-222, 1c-1, 1c-2, 1c-3, 1c-4, 1c-5, 1c-6, 1c-7, 1c-9, 1c-10,1c-11, 9-12, 9-16, 9-32, 9-48, and 9-55; each of which are respectivelynamed herein. In yet another aspect of the invention, are compounds thathad an MED≤1 μM against H. contortus L3 larvae including 1 b-18, 1b-23,1b-66, 1b-89, 1b-94, 1b-96, 1b-104, 1b-108, 1b-115, 1b-151, 1b-160,1b-165, 1b-171, 1b-173, 1b-176, 1b-177, 1b-206, 1b-211, 1b-212, 1b-215,1b-216, 1b-217, 1b-219, and 1b-222; each of which are respectively namedherein. In yet another aspect of the invention, are compounds that hadan MED>1 to ≤10 μM against H. contortus L3 larvae including: 1a-10,1a-14, 1a-16, 1a-17, 1a-20, 1a-21, 1a-26, 1a-31, 1a-35, 1a-36, 1a-37,1b-16, 1b-17, 1b-19, 1b-21, 1b-24, 1b-29, 1b-46, 1b-52, 1b-95, 1b-110,1b-118, 1b-126, 1b-127, 1b-129, 1b-143, 1b-145, 1b-166, 1b-179, 1b-186,1b-187, 1b-190, 1b-197, 1b-201, 1b-207, 1b-210, 1b-213, 1b-214, 1b-221,2-1, 2-2, 2-7, 2-19, 2-22, 2-28, 2-30, 2-45, 2-51, 2-53, 2-66, 2-68,2-69, 2-74, 2-79, 2-87, 3-1, 3-2, 3-3, 3-27, 6-3, 6-7, 6-9, 6-12, 6-20,7-9, 8-3, 8-4, 8-6, 8-7, 8-8, 8-9, 8-13, 8-15, 9-1, 9-6, 9-11, 9-22,9-28, 9-34, 9-41, 9-50, 9-51, 9-52, 9-53, 9-54, 9-56, 9-57, 9-59, 10-3,10-6, 10-11, 10-13, 10-17, 10-18, 10-30, and 10-31; each of which arerespectively named herein.

In yet another aspect of the invention, is a composition comprising aFormula (1) compound, stereoisomer thereof, and veterinary acceptablesalt thereof. In yet another aspect of the invention is a compositioncomprising a Formula (1) compound, stereoisomer thereof, and veterinaryacceptable salt thereof, and further comprising a veterinary acceptableexcipient. In yet another aspect of the invention is a compositioncomprising a Formula (1) compound, stereoisomer thereof, and veterinaryacceptable salt thereof, and further comprising a veterinary acceptableexcipient, and optionally, at least one additional antiparasitic agent.In yet another aspect of the invention is a composition comprising aFormula (1) compound, stereoisomer thereof, and veterinary acceptablesalt thereof, and further comprising a veterinary acceptable excipientand at least one additional antiparasitic agent.

In yet another aspect of the invention, is a composition comprising aFormula (1A) compound, stereoisomer thereof, and veterinary acceptablesalt thereof. In yet another aspect of the invention is a compositioncomprising a Formula (1A) compound, stereoisomer thereof, and veterinaryacceptable salt thereof, and further comprising a veterinary acceptableexcipient. In yet another aspect of the invention is a compositioncomprising a Formula (1A) compound, stereoisomer thereof, and veterinaryacceptable salt thereof, and further comprising a veterinary acceptableexcipient, and optionally, at least one additional antiparasitic agent.In yet another aspect of the invention is a composition comprising aFormula (1A) compound, stereoisomer thereof, and veterinary acceptablesalt thereof, and further comprising a veterinary acceptable excipientand at least one additional antiparasitic agent.

In yet another aspect of the invention, is a composition comprising aFormula (1A1) compound, stereoisomer thereof, and veterinary acceptablesalt thereof. In yet another aspect of the invention is a compositioncomprising a Formula (1A1) compound, stereoisomer thereof, andveterinary acceptable salt thereof, and further comprising a veterinaryacceptable excipient. In yet another aspect of the invention is acomposition comprising a Formula (1A1) compound, stereoisomer thereof,and veterinary acceptable salt thereof, and further comprising aveterinary acceptable excipient, and optionally, at least one additionalantiparasitic agent. In yet another aspect of the invention is acomposition comprising a Formula (1A1) compound, stereoisomer thereof,and veterinary acceptable salt thereof, and further comprising aveterinary acceptable excipient and at least one additionalantiparasitic agent.

In yet another aspect of the invention, is a composition comprising aFormula (1A1-1) compound, stereoisomer thereof, and veterinaryacceptable salt thereof. In yet another aspect of the invention is acomposition comprising a Formula (1A1-1) compound, stereoisomer thereof,and veterinary acceptable salt thereof, and further comprising aveterinary acceptable excipient. In yet another aspect of the inventionis a composition comprising a Formula (1A1-1) compound, stereoisomerthereof, and veterinary acceptable salt thereof, and further comprisinga veterinary acceptable excipient, and optionally, at least oneadditional antiparasitic agent. In yet another aspect of the inventionis a composition comprising a Formula (1A1-1) compound, stereoisomerthereof, and veterinary acceptable salt thereof, and further comprisinga veterinary acceptable excipient and at least one additionalantiparasitic agent. In yet another aspect of the invention, is acomposition comprising a Formula (1A1-1) compound described in Table 1b,stereoisomer thereof, and veterinary acceptable salt thereof. In yetanother aspect of the invention is a composition comprising a Formula(1A1-1) compound, described in Table 1b, stereoisomer thereof, andveterinary acceptable salt thereof, and further comprising a veterinaryacceptable excipient. In yet another aspect of the invention is acomposition comprising a Formula (1A1-1) compound described in Table 1b,stereoisomer thereof, and veterinary acceptable salt thereof, andfurther comprising a veterinary acceptable excipient, and optionally, atleast one additional antiparasitic agent. In yet another aspect of theinvention is a composition comprising a Formula (1A1-1) compounddescribed in Table 1b, stereoisomer thereof, and veterinary acceptablesalt thereof, and further comprising a veterinary acceptable excipientand at least one additional antiparasitic agent. In yet another aspectof the invention, is a composition comprising a Formula (1A1-2)compound, stereoisomer thereof, and veterinary acceptable salt thereof.In yet another aspect of the invention is a composition comprising aFormula (1A1-2) compound, stereoisomer thereof, and veterinaryacceptable salt thereof, and further comprising a veterinary acceptableexcipient. In yet another aspect of the invention is a compositioncomprising a Formula (1A1-2) compound, stereoisomer thereof, andveterinary acceptable salt thereof, and further comprising a veterinaryacceptable excipient, and optionally, at least one additionalantiparasitic agent. In yet another aspect of the invention is acomposition comprising a Formula (1A1-2) compound, stereoisomer thereof,and veterinary acceptable salt thereof, and further comprising aveterinary acceptable excipient and at least one additionalantiparasitic agent. In yet another aspect of the invention, is acomposition comprising a Formula (1A1-3) compound, stereoisomer thereof,and veterinary acceptable salt thereof. In yet another aspect of theinvention is a composition comprising a Formula (1A1-3) compound,stereoisomer thereof, and veterinary acceptable salt thereof, andfurther comprising a veterinary acceptable excipient. In yet anotheraspect of the invention is a composition comprising a Formula (1A1-3)compound, stereoisomer thereof, and veterinary acceptable salt thereof,and further comprising a veterinary acceptable excipient, andoptionally, at least one additional antiparasitic agent. In yet anotheraspect of the invention is a composition comprising a Formula (1A1-3)compound, stereoisomer thereof, and veterinary acceptable salt thereof,and further comprising a veterinary acceptable excipient and at leastone additional antiparasitic agent.

In yet another aspect of the invention, is a composition comprising aFormula (1B), (1C), or (1D) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention is a composition comprising a Formula (1B), (1C), or (1D)compound, stereoisomer thereof, and veterinary acceptable salt thereof,and further comprising a veterinary acceptable excipient. In yet anotheraspect of the invention is a composition comprising a Formula (1B),(1C), or (1D) compound, stereoisomer thereof, and veterinary acceptablesalt thereof, and further comprising a veterinary acceptable excipient,and optionally, at least one additional antiparasitic agent. In yetanother aspect of the invention is a composition comprising a Formula(1B), (1C), or (1D) compound, stereoisomer thereof, and veterinaryacceptable salt thereof, and further comprising a veterinary acceptableexcipient and at least one additional antiparasitic agent.

In yet another aspect of the invention, is a composition comprising aFormula (1B1), (1C1), (1D1), or (1E1) compound, stereoisomer thereof,and veterinary acceptable salt thereof. In yet another aspect of theinvention is a composition comprising a Formula (1B1), (1C1), (1D1), or(1E1) compound, stereoisomer thereof, and veterinary acceptable saltthereof, and further comprising a veterinary acceptable excipient. Inyet another aspect of the invention is a composition comprising aFormula (1B1), (1C1), (1D1) or (1E1) compound, stereoisomer thereof, andveterinary acceptable salt thereof, and further comprising a veterinaryacceptable excipient, and optionally, at least one additionalantiparasitic agent. In yet another aspect of the invention is acomposition comprising a Formula (1B1), (1C1), (1D1), or (1E1) compound,stereoisomer thereof, and veterinary acceptable salt thereof, andfurther comprising a veterinary acceptable excipient and at least oneadditional antiparasitic agent.

In yet another aspect of the invention, is a composition comprising aFormula (1B1-1), (1C1-1), or (1D1-1) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention is a composition comprising a Formula (1B1-1), (1C1-1), or(1D1-1) compound, stereoisomer thereof, and veterinary acceptable saltthereof, and further comprising a veterinary acceptable excipient. Inyet another aspect of the invention is a composition comprising aFormula (1B1-1), (1C1-1), or (1D1-1) compound, stereoisomer thereof, andveterinary acceptable salt thereof, and further comprising a veterinaryacceptable excipient, and optionally, at least one additionalantiparasitic agent. In yet another aspect of the invention is acomposition comprising a Formula (1B1-1), (1C1-1), or (1D1-1) compound,stereoisomer thereof, and veterinary acceptable salt thereof, andfurther comprising a veterinary acceptable excipient and at least oneadditional antiparasitic agent.

In yet another aspect of the invention, is a composition comprising aFormula (1B1-2) or (1C1-2) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention is a composition comprising a Formula (1B1-2) or (1C1-2)compound, stereoisomer thereof, and veterinary acceptable salt thereof,and further comprising a veterinary acceptable excipient. In yet anotheraspect of the invention is a composition comprising a Formula (1B1-2) or(1C1-2) compound, stereoisomer thereof, and veterinary acceptable saltthereof, and further comprising a veterinary acceptable excipient, andoptionally, at least one additional antiparasitic agent. In yet anotheraspect of the invention is a composition comprising a Formula (1B1-2) or(1C1-2) compound, stereoisomer thereof, and veterinary acceptable saltthereof, and further comprising a veterinary acceptable excipient and atleast one additional antiparasitic agent.

In yet another aspect of the invention, is a composition comprising aFormula (1E1), (1F1) or (1F2) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention is a composition comprising a Formula (1E1), (1F1) or (1F2)compound, stereoisomer thereof, and veterinary acceptable salt thereof,and further comprising a veterinary acceptable excipient. In yet anotheraspect of the invention is a composition comprising a Formula (1E1),(1F1) or (1F2) compound, stereoisomer thereof, and veterinary acceptablesalt thereof, and further comprising a veterinary acceptable excipient,and optionally, at least one additional antiparasitic agent. In yetanother aspect of the invention is a composition comprising a Formula(1E1), (1F1) or (1F2) compound, stereoisomer thereof, and veterinaryacceptable salt thereof, and further comprising a veterinary acceptableexcipient and at least one additional antiparasitic agent.

In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1A)compound, stereoisomer thereof, and veterinary acceptable salt thereof.In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1A1) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1A1-1)compound, stereoisomer thereof, and veterinary acceptable salt thereof.In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1A1-1) compound described in Table 1a,stereoisomer thereof, and veterinary acceptable salt thereof. In yetanother aspect of the invention, is a method of treating a parasiticinfection in an animal in need thereof by administering an effectiveamount of a Formula (1A1-1) compound described in Table 1b, stereoisomerthereof, and veterinary acceptable salt thereof.

In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1A1-2) compound, stereoisomer thereof,and veterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1A1-3)compound, stereoisomer thereof, and veterinary acceptable salt thereof.

In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1B) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1B1)compound, stereoisomer thereof, and veterinary acceptable salt thereof.In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1B1-1) compound, stereoisomer thereof,and veterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1B1-2)compound, stereoisomer thereof, and veterinary acceptable salt thereof.

In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1C) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1C1)compound, stereoisomer thereof, and veterinary acceptable salt thereof.In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1C1-1) compound, stereoisomer thereof,and veterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1C1-2)compound, stereoisomer thereof, and veterinary acceptable salt thereof.

In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1D) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1D1)compound, stereoisomer thereof, and veterinary acceptable salt thereof.In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1D1-1) compound, stereoisomer thereof,and veterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1E1)compound, stereoisomer thereof, and veterinary acceptable salt thereof.In yet another aspect of the invention, is a method of treating aparasitic infection in an animal in need thereof by administering aneffective amount of a Formula (1F1) compound, stereoisomer thereof, andveterinary acceptable salt thereof. In yet another aspect of theinvention, is a method of treating a parasitic infection in an animal inneed thereof by administering an effective amount of a Formula (1F2)compound, stereoisomer thereof, and veterinary acceptable salt thereof.

In another aspect of the invention, the method of treating a parasiticinfection in an animal in need thereof which comprises administering aneffective amount of a Formula (1), Formula (1A), Formula (1A1), Formula(1A1-1), Formula (1A1-2), Formula (1A1-3), Formula (1B), Formula (1B1),Formula (1B1-1), Formula (1B1-2), Formula (10), Formula (1C1), Formula(1C1-1), Formula (1C1-2), Formula (1D), Formula (1D1), Formula (1D1-1),Formula (1E1), Formula (1F1), or Formula (1F2) compound. In anotheraspect of the invention, the method of treating a parasitic infection inan animal in need thereof which comprises administering an effectiveamount of a compound of Formula (1A1), Formula (1A1-1), or Formula(1A1-2). In another aspect of the invention, the method of treating aparasitic infection in an animal in need thereof which comprisesadministering an effective amount of a compound of Formula (1A1-1). Inanother aspect of the invention, the method of treating a parasiticinfection in an animal in need thereof which comprises administering aneffective amount of a compound of Formula (1A1-1) described in Table 1a.In another aspect of the invention, the method of treating a parasiticinfection in an animal in need thereof which comprises administering aneffective amount of a compound of Formula (1A1-1) described in Table 1b.In another aspect of the invention, the method of treating a parasiticinfection in an animal in need thereof which comprises administering aneffective amount of a compound of Formula (1A1-2). In another aspect ofthe invention, the method of treating a parasitic infection in an animalin need thereof which comprises administering an effective amount of acompound of Formula (1F1). The term “administering”, as described above,includes oral, topical, and injectable means. Injectable includessubcutaneous, intramuscular, and intravenous injection. The term“animal”, as described above, includes companion animals. Preferred,companion animal refers to canine. The term “parasitic infection”, asdescribed above, refers to an endoparasitic infection, preferably anendoparasitic infection caused by a filarial parasite. In certainaspects, the filarial parasite is Dirofilaria immitis (heartworm).

In yet another aspect of the invention, is the use of a Formula (1),Formula (1A), Formula (1A1), Formula (1A1-1), Formula (1A1-1; Table 1a),Formula (1A1-1; Table 1b), Formula (1A1-2), Formula (1A1-3), Formula(1B), Formula (1B1), Formula (1B1-1), Formula (1B1-2), Formula (1C),Formula (1C1), Formula (1C1-1), Formula (1C1-2), Formula (1D), Formula(1D1), Formula (1D1-1), Formula (1E1), Formula (1F1), or Formula (1F2)compound to treat a parasitic infection in an animal in need thereof. Inyet another aspect of the invention, is the use of a Formula (1A),Formula (1A1), Formula (1A1-1), Formula (1A1-1; Table 1a), Formula(1A1-1; Table 1b), Formula (1A1-2), or Formula (1F1) compound to treat aparasitic infection in an animal in need thereof. In yet another aspectof the invention, is the use of a Formula (1A1) compound to treat aparasitic infection in an animal in need thereof. In yet another aspectof the invention, is the use of a Formula (1A1-1) compound to treat aparasitic infection in an animal in need thereof. In yet another aspectof the invention, is the use of a Formula (1A1-1) compound described inTable 1a to treat a parasitic infection in an animal in need thereof. Inyet another aspect of the invention, is the use of a Formula (1A1-1)compound described in Table 1b to treat a parasitic infection in ananimal in need thereof. In yet another aspect of the invention, is theuse of a Formula (1A1-2) compound to treat a parasitic infection in ananimal in need thereof.

In yet another aspect of the invention, is the use of a Formula (1),Formula (1A), Formula (1A1), Formula (1A1-1), Formula (1A1-1; Table 1a),Formula (1A1-1; Table 1b), Formula (1A1-2), Formula (1A1-3), Formula(1B), Formula (1B1), Formula (1B1-1), Formula (1B1-2), Formula (1C),Formula (1C1), Formula (1C1-1), Formula (1C1-2), Formula (1D), Formula(1D1), Formula (1D1-1), Formula (1E1), Formula (1F1), or Formula (1F2)compound to prepare a medicament for treating a parasitic infection inan animal in need thereof. In yet another aspect of the invention, isthe use of a Formula (1A), Formula (1A1), Formula (1A1-1), Formula(1A1-1; Table 1a), Formula (1A1-1; Table 1b), Formula (1A1-2), orFormula (1F1) compound to prepare a medicament for treating a parasiticinfection in an animal in need thereof. In yet another aspect of theinvention, is the use of a Formula (1A1) compound to prepare amedicament for treating a parasitic infection in an animal in needthereof. In yet another aspect of the invention, is the use of a Formula(1A1-1) compound to prepare a medicament for treating a parasiticinfection in an animal in need thereof. In yet another aspect of theinvention, is the use of a Formula (1A1-1) compound described in Table1a to prepare a medicament for treating a parasitic infection in ananimal in need thereof. In yet another aspect of the invention, is theuse of a Formula (1A1-1) compound described in Table 1b to prepare amedicament for treating a parasitic infection in an animal in needthereof.

In yet another aspect of the invention, is the use of a Formula (1A1-2)compound to prepare a medicament for treating a parasitic infection inan animal in need thereof. In yet another aspect of the invention, isthe use of a Formula (1F1) compound to prepare a medicament for treatinga parasitic infection in an animal in need thereof.

The compounds of the invention are intended to encompass racemicmixtures, specific stereoisomers, regional-isomers, and tautomeric formsof the compound

DETAILED DESCRIPTION Definitions

For purposes of the present invention, as described and claimed herein,the following terms and phrases are defined as follows:

“Additional veterinary agent(s)” as used herein, refers to otherveterinary or veterinary compounds or products that provide atherapeutically effective amount of said agents that are useful for thetreatment of a parasitic infection in an animal, as described herein.

“Alkoxy”, as used herein, refers to alkyl-O—, wherein the term alkyl isdefined below. Non-limiting alkoxy examples include: methoy, ethoxy,propoxy, isopropoxy, n-butoxy, n-pentoxy, 1-methylbutoxy,1-ethylpropoxy, and the like.

“Alkyl”, as used herein, unless otherwise indicated, refers to saturatedmonovalent hydrocarbon alkane radicals of the general formulaC_(n)H_(2n+1). The alkane radical may be straight or branched and may beunsubstituted or substituted. For example, the term “(C₁-C₆)alkyl”refers to a monovalent, straight or branched aliphatic group containing1 to 6 carbon atoms. Non-exclusive examples of (C₁-C₆) alkyl groupsinclude, but are not limited to methyl, ethyl, propyl, isopropyl,sec-butyl, t-butyl, n-propyl, n-butyl, i-butyl, s-butyl, n-pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl,3,3-dimethylpropyl, 2-methylpentyl, hexyl, and the like. The alkylmoiety may be attached to the chemical moiety by any one of the carbonatoms of the aliphatic chain. Alkyls are optionally substituted asdescribed herein.

“Alkenyl” as used herein, unless otherwise indicated, refers to astraight or branched aliphatic hydrocarbon chain having 2- to 6-carbonatoms and containing at least one carbon-carbon double bond (for example—C═C—). Non-exclusive examples of alkenyl include: ethenyl, 1-propenyl,2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl,and the like. Alkenyls are optionally substituted as described herein.

“Alkynyl” as used herein, unless otherwise indicated, refers to straightor branched aliphatic hydrocarbon chain having 2- to 6-carbon atoms andcontaining at least one carbon-carbon triple bond (for example, —C≡C— or—C≡CH). Non-exclusive examples of alkynyl include: ethynyl, 2-propynyl,1-methyl-2-propynyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl, and thelike. Alkynyls are optionally substituted as described herein.

“Animal(s)”, as used herein, unless otherwise indicated, refers to anindividual animal that is a mammal or bird. Specifically, mammal refersto a vertebrate animal that is human and non-human, which are members ofthe taxonomic class Mammalia. Non-exclusive examples of non-humanmammals include companion animals and livestock. Non-exclusive examplesof a companion animal include: dog, cat, llama, and horse. Preferredcompanion animals are dog, cat, and horse. More preferred is dog.Non-exclusive examples of livestock include: swine, camel, rabbits,goat, sheep, deer, elk, bovine (cattle), and bison. Preferred livestockis cattle and swine. Specifically, bird refers to a vertebrate animal ofthe taxonomic class Ayes. Birds are feathered, winged, bipedal,endothermic, and egg-laying. Non-exclusive examples of bird include,poultry (e.g., chicken, turkey, duck, and geese), all of which are alsoreferred to herein as fowl.

“Aryl”, as described herein, refers to a monovalent aromatic carbocyclicgroup of from 6 to 10 carbon atoms having a single ring or multiplefused rings. Aryl groups include, but are not limited to, phenyl,biphenyl, and naphthyl. Aryls are optionally substituted as describedherein.

“Chiral”, as used herein, unless otherwise indicated, refers to thestructural characteristic of a molecule that makes it impossible tosuperimpose it on its mirror image, (e.g., “R” and “S” enantiomers).

“Comprise(s)”, as used herein, refers to an inclusive meaning, i.e.,that it will be taken to mean an inclusion of not only the listedcomponents it directly references, but also other non-specifiedcomponents or elements. This rationale will also be used when the term“comprised” or “comprising” is used in relation to one or more Steps ina method or process. Contains is herein construed as being synonymous tocomprise. The term “consisting of”, and/or “consisting essentially of”has a non-inclusive meaning.

“Compounds of the present invention”, as used herein, unless otherwiseindicated, refers to compounds of Formula (1), stereoisomers thereof,and veterinary acceptable salts thereof. The term and/or phrase alsorefer to the sub-genus formulas of Formula (1) including: Formula (1A1),Formula (1A1-1), Formula (1A1-2), Formula (1B1), Formula (1B1-1),Formula (1B1-2), Formula (1C1), Formula (1C1-1), Formula (1C1-2),Formula (1D1), Formula (1D1-1), Formula (1E1), and Formula (1E2),stereoisomers thereof, and veterinary acceptable salts thereof.Synonymously, the compounds of the present invention are described asdepsipeptide(s) and octadepsipeptide(s).

“Cycloalkyl”, as used herein, unless otherwise indicated, includes fullysaturated or partially saturated carbocyclic alkyl moieties.Non-limiting examples of partially saturated cycloalkyls include:cyclopropene, cyclobutene, cycloheptene, cyclooctene,cyclohepta-1,3-diene, and the like. Preferred cycloalkyls are 3- to6-membered saturated monocyclic rings including cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. The cycloalkyl group may be attached to thechemical moiety by any one of the carbon atoms within the carbocyclicring. Cycloalkyl groups are optionally substituted as described herein.

“Halogen” or “halo”, as used herein, unless otherwise indicated, refersto fluorine, chlorine, bromine and iodine. Further, when used incompound words such as “haloalkyl”, “haloalkoxy”, “haloalkenyl”, or“haloalkynyl”, said alkyl, alkoxy, alkenyl, and alkynyl may be partiallyor fully substituted with halogen atoms which may be the same ordifferent and said alkyl, alkoxy, alkenyl, and alkynyl moiety has thesame meaning as above and may be attached to the chemical moiety by anyone of the carbon atoms of the aliphatic chain. Examples of haloalkylinclude F₃C—, F₂CH—ClCH₂—, CF₃CH₂— and CF₂CCl₂—, and the like. The term“haloalkoxy” is defined analogously to the term “haloalkyl”. Examples ofhaloalkoxy include CF₃O—, CCl₃CH₂O—, HCF₂CH₂CH₂O— and CF₃CH₂O—, and thelike.

“Het”, as used herein, unless otherwise indicated, refers to heteroarylor heterocycle; each as described herein.

“Heteroaryl”, as used herein, unless otherwise indicated, refers to a 5-to 6-membered aromatic monocyclic ring or an 8- to 11-membered fusedaromatic ring where said monocyclic- and fused-ring moiety contains oneor more heteroatoms each independently selected from N, O, or S,preferably from one to four heteroatoms. Non-exclusive examples ofmonocyclic heteroaryls include pyrrolyl, furanyl, thiophenyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, and the like. Preferred monocyclic heteroaryls includepyrazole, imidazole, and triazole. More preferred monocyclic heteroarylsare pyrazoles and imidazoles. A more preferred monocyclic heteroaryl ispyrazole. A more preferred monocyclic heteroaryl is imidazole.Non-exclusive examples of fused heteroaryls include: benzofuranyl,benzothiophenyl, indolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazole),indazolyl, pyrrolopyrazolyl (e.g., 5,6-dihydropyrrolo[3,4-c]pyrazole,6,7-dihydropyrano[4,3-c]pyrazole, 5,6-dihydropyrrolo[3,4-c]pyrazole),benzoxazines (e.g., 2,3-dihydro-4H-benzo[b][1,4]oxazine), benzothiazines(e.g., 2,3-dihydro-4H-benzo[b][1,4]thiazine), pyridooxazines (e.g.,2,3-dihydropyrido[2,3-b][1,4]oxazine,2,3-dihydropyrido[4,3-b][1,4]oxazine,2,3-dihydropyrido[3,2-b][1,4]oxazine), pyridothiazines (e.g.,2,3-dihydropyrido[2,3-b][1,4]thiazine, pyrido[3,2-b][1,4]thiazine),quinoxalines (e.g., 2,3-dihydroquinoxaline, 3,4-dihydro-2H-quinoxaline),quinolinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazole),thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole,pyrrolopyridine (e.g., 1H-pyrrolo[2,3-b]pyridine;1H-pyrrolo[2,3-c]pyridine), tetrahydrocyclopentalpyrazole (e.g.,1,4,5,6-tetrahydrocyclopenta[c]pyrazole,2,4,5,6-tetrahydrocyclopenta[c]pyrazole),5,6-dihydrocyclopenta[c]pyrazole, 1H-pyrazolo[3,4-b]pyridine, and thelike. The heteroaryl ring is attached to the chemical moiety by any oneof the nitrogen heteroatoms within the monocyclic or fused ring.Heteroaryls are optionally substituted as described herein.

“Heterocycle”, as used herein, unless otherwise indicated, refers to apartially saturated or saturated 4- to 6-membered monocyclic ring, 8- to11-membered fused ring, each containing one or more heteroatomsindependently selected from N, O, or S, preferably from one to fourheteroatoms. Non-exclusive examples of heterocycle include oxirane,thiarane, aziridine, oxetane, azetidine, thiatane, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, morpholine, thiomorpholine,tetrahydropyrane, piperidine, piperazine, tetrahydropyridine,2H-azirine, 2,3-dihydro-azete, 3,4-dihydro-2H-pyrrole, azathiane,oxazinane, imidazolidine, oxazolidine, isoxazolidine,1,2-dihydropyridine, and the like. The heterocyclic ring is attached tothe chemical moiety by any one of the nitrogen heteroatoms within themonocyclic or fused ring. Heterocycles are optionally substituted asdescribed herein.

“Optionally substituted”, is used herein interchangeably with the phrasesubstituted or unsubstituted. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and each substitution is independent of the other. Anoptionally substituted group also may have no substituents. Therefore,the phrase “optionally substituted with at least one substituent” meansthat the number of substituents may vary from zero up to a number ofavailable positions for substitution.

“Parasite(s)”, as used herein, unless otherwise indicated, refers toendoparasites and ectoparasites. Endoparasites are parasites that livewithin the body of its host and include helminths (e.g., trematodes,cestodes, and nematodes) and protozoa. Ectoparasites are organisms ofthe Arthropoda phylum (e.g., arachnids, insects, and crustaceans (e.g.,copepods-sea lice) which feed through or upon the skin of its host.Preferred arachnids are of the order Acarina, e.g., ticks and mites.Preferred insects are midges, fleas, mosquitos, biting flies (stablefly, horn fly, blow fly, horse fly, and the like), bed bugs, and lice.Preferred compounds of the present invention can be used for thetreatment of parasites, i.e., treatment of a parasitic infection orinfestation.

“Percent” (%), as used herein, refers to individual percent values. Whenreferring to % in liquids (volume/volume % or v/v %) like an aqueousorganic solvent, the % is the volume % of the solvent in the totalvolume of the solution. When referring to % for solids in liquids(weight/volume % or w/v %), the % value is construed to be the weight ofthe solid in the total volume of the solution and refers to the numberof grams of solute in 100 mL of solution. When referring to solids(weight % or w/w %) refers to the weight (mass) of one componentrelative to the total weight (mass) of the solid composition.

“Protecting group” or “Pg”, as used herein, unless otherwise indicated,refers to a substituent that is commonly employed to block or protect anamine on the compound thereby protecting its functionality whileallowing for the reaction of other functional groups on the compound.Non-exclusive examples of an amine-protecting group include: acyl groups(e.g., formyl, acetyl, chloroacetyl, trichloro-acetyl,o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl,4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl,acylisothiocyanate, aminocaproyl, benzoyl, and the like), acyloxy groups(e.g., 1-tert-butyloxycarbonyl (Boc), methoxycarbonyl,9-fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,1,1-dimethyl-propynyloxycarbonyl, benzyloxy-carbonyl,p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and the like),diphenylmethane, and benzylcarbamates.

“Substituted”, as used herein, refers to a substituent that is bonded tothe chemical moiety in place of a hydrogen atom. Common substituents ofthe invention for alkyl, cycloalkyl, aryl, heterocyle, heteroarylmoieties, an d the like, are as described herein, and include, forexample, —NO₂, —CN, alkyl, halo, alkoxy, haloalkyl, haloalkoxy,cycloalkyl, hydroxy, amino, alkylamino, dialkylamino, and the like.Substituents can be bonded to any carbon in the aliphatic chain orcarbocyclic, aryl, heterocyclic, or heteroaryl ring system. Thesubstituent can also be bonded to any accepting nitrogen and/or sulfuratom.

“Therapeutically effective amount”, as used herein, refers to an amountof the active agent (i.e., Formula (1) compound) that (i) treat theparticular parasitic infection or infestation, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particularparasitic infection or infestation, or (iii) prevents or delays theonset of one or more symptoms of the particular parasitic infection orinfestation described herein. The active agent may be in a compositionsufficient to elicit the desired biological response to the targetparasite(s) after administration of the composition to the animal, asmeasured by methods known in the art and/or described in the examplesherein. In some instances, an “effective amount” of the active agent inthe composition will provide an efficacy of at least 70% against thetarget parasite compared to an untreated control. In other instances,“an effective amount” of the active agent will provide an efficacy of atleast 80%, or at least 85% compared to untreated controls. Moretypically, “an effective amount” of the active agent will provide anefficacy of at least 90%, at least 93%, at least 95% or at least 97%against the target parasite. In certain instances, including theprevention of Dirofilaria immitis, the term “effective amount” mayprovide efficacy as high as 100%. As is understood in the art, atherapeutically effective amount may be in one or more doses, i.e., asingle dose or multiple doses may be required to achieve the desiredtreatment endpoint, for example, (i) treat the particular parasiticinfection or infestation, (ii) attenuates, ameliorates, or eliminatesone or more symptoms of the particular parasitic infection orinfestation, or (iii) prevents or delays the onset of one or moresymptoms of the particular parasitic infection or infestation describedherein. The therapeutically effective amount will vary depending on thecompound, the disease and its severity and the age, weight, etc., of themammal to be treated.

“Treatment”, “treating”, and the like, as used herein, unless otherwiseindicated, refers to reversing, alleviating, or inhibiting the parasiticinfection, infestation, or condition. As used herein, these terms alsoencompass, depending on the condition of the animal, preventing theonset of a disorder or condition, or of symptoms associated with adisorder or condition, including reducing the severity of a disorder orcondition or symptoms associated therewith prior to affliction with saidinfection or infestation or after said infection or infestation. Thus,treatment can refer to administration of the compounds of the presentinvention to an animal that is not at the time of administrationafflicted with the infection or infestation. Treating also encompassespreventing the recurrence of an infection or infestation or of symptomsassociated therewith as well as references to “control” (e.g., kill,repel, expel, incapacitate, deter, eliminate, alleviate, minimize, anderadicate).

“Veterinary acceptable” as used herein, unless otherwise indicated,indicates that the substance or composition must be compatiblechemically and/or toxicologically, with the other ingredients comprisinga formulation, composition, and/or the animal being treated therewith.

The Formula (1) compounds of the invention are 24-membered cyclicdepsipeptide compounds which have potent activity against endoparasitessuch as nematodes and filarial worms (microfilarial and larval stages)and also in some cases against ectoparasites such as fleas and ticks. Inone aspect of the invention is a cyclic depsipeptide of Formula (1), ora veterinarily acceptable salt thereof. Surprisingly, it has been foundthat addition of a methylene linker between the aryl ring in one or bothof the phenyl lactate groups in the molecule versus the parent cyclicdepsipeptide PF1022 and emodepside, improves the selectivity andactivity of the compounds against parasites, particularly,endoparasites. This improvement provides selectivity against the L3 andL4 larvae and the actual microfilaria by killing the L3 and L4 larvaebefore metamorphosis into the next lifecycle change, the animal ishealthier and does not need to succumb to the killing of microfilaria oradult worms which can cause emboli and ultimately death to the hostanimal. Furthermore, it has been surprisingly found that substitution ofthe compounds of Formula (1) with certain L1 and L2 groups alsosignificantly improves the in vitro metabolic stability of the compoundsof the invention compared with PF1022 and emodepside. Thus, thecompounds of the invention have been found to have significantlyimproved metabolic stability and equal or significantly improvedefficacy against endoparasites including Dirofilaria immitismicrofilaria and/or L3 and L4 larvae and/or Haemonchus contortus larvae.In some aspects, the compounds of Formula (1) with certain substituentswill also exhibit improved activity against ectoparasites.

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, “Reagents for Organic Synthesis”, 1; 19, Wiley, New York (1967,1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database)). For illustrative purposes, the reactionschemes depicted below demonstrate potential routes for synthesizingcompounds of the present invention, and key intermediates. For a moredetailed description of the individual reaction Steps, see the Examplessection below. A skilled artisan will appreciate that other suitablestarting materials, reagents, and synthetic routes may be used tosynthesize the compounds of the present invention and a variety ofderivatives thereof. Further, many of the compounds prepared by themethods described below can be further modified in light of thisdisclosure using conventional chemistry well known to the skilledartisan.

The depsipeptides of the present invention described herein, include oneor more chiral centers which results in a theoretical number ofoptically active isomers. Where compounds of the invention include nchiral centers, the compounds may comprise up to 2n optical isomers. Thepresent invention encompasses the specific enantiomers or diastereomers,and mixtures thereof, of each compound. The optically active forms canbe prepared by, for example, resolution of the racemic forms byselective crystallization techniques, by synthesis from optically activeprecursors, by chiral synthesis, by chromatographic separation using achiral stationary phase or by enzymatic resolution. The depsipeptides ofthe present invention include their respective stereoisomers.

For illustrative purposes, the reaction schemes depicted belowdemonstrate potential routes for synthesizing key intermediates andcompounds of the present invention. For a more detailed description ofthe individual reaction steps, see the Examples section below. Thoseskilled in the art will appreciate that other suitable startingmaterials, reagents, and synthetic routes may be used to synthesize theintermediates and compounds of the present invention and a variety ofderivatives thereof. Further, many of the compounds prepared by themethods described below can be further modified in light of thisdisclosure using conventional chemistry. Schemes 1-3 outline the generalprocedures useful for the preparation and isolation of compounds of thepresent invention. It is to be understood, however, that the invention,as fully described herein and as recited in the claims, is not intendedto be limited by the details of the following schemes or modes ofpreparation. In the preparation of compounds of the present invention,protection of remote functionality of intermediates from undesiredreactions can be accomplished with a protecting group.

In the preparation of compounds of the present invention, protection ofremote functionality of intermediates from undesired reactions can beaccomplished with a protecting group. The term “protecting group” or“Pg” refers to a substituent that is commonly employed to block orprotect a particular functionality while reacting other functionalgroups on the compound. For example, an amine-protecting group is asubstituent attached to an amine that blocks or protects theamine-functionality of the compound or intermediate. Suitable amineprotecting groups include: 1-tert-butyloxycarbonyl (Boc), acyl groupsincluding: formyl, acetyl, chloroacetyl, trichloro-acetyl,o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl,4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl,acylisothiocyanate, aminocaproyl, benzoyl, and the like; and acyloxygroups including: methoxycarbonyl, 9-fluorenyl-methoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl,vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethyl-propynyloxycarbonyl,benzyloxy-carbonyl, p-nitrobenzyloxycarbony,2,4-dichlorobenzyloxycarbonyl, and the like. Similarly, diphenylmethaneand benzylcarbamates can be used as amine protecting groups. Suitableprotecting groups and their respective uses are readily determined byone skilled in the art. For a general description of protecting groupsand their use, see T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York, 1991.

The compounds of the invention are intended to encompass racemicmixtures, specific stereoisomers and tautomeric forms of the compound.Another aspect of the invention is a salt form of the compound of theinvention.

The compounds of present invention may also be present in differentsolid forms such as different crystalline forms or in the form of anamorphous solid. The present invention encompasses different crystallineforms as well as amorphous forms of the inventive compounds.

In addition, the compounds of the invention may exist as hydrates orsolvates, in which a certain stoichiometric amount of water or a solventis associated with the molecule in the crystalline form. The hydratesand solvates of the compounds of formula (I) are also the subject of theinvention.

In addition to the neutral compounds of Formula (1), salt forms of thecompounds are also active against endoparasites. The term “veterinaryacceptable salt” is used throughout the specification to describe anysalts of the compounds that are acceptable for administration forveterinary applications, and which provides the active compound uponadministration.

In cases where compounds are sufficiently basic or acidic to form stablenon-toxic acid or base salts, the compounds may be in the form of aveterinary or agriculturally acceptable salt. Veterinary acceptablesalts include those derived from veterinary or agriculturally acceptableinorganic or organic bases and acids. Suitable salts include thosecomprising alkali metals such as lithium, sodium or potassium, alkalineearth metals such as calcium, magnesium and barium. Salts comprisingtransition metals including, but not limited to, manganese, copper, zincand iron are also suitable. In addition, salts comprising ammoniumcations (NH₄ ₊ ) as well as substituted ammonium cations, in which oneor more of the hydrogen atoms are replaced by alkyl or aryl groups areencompassed by the invention.

Salts derived from inorganic acids including, but not limited to,hydrohalide acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid,phosphoric acid, and the like are particularly suitable. Suitableinorganic salts also include, but not limited to, bicarbonate, andcarbonate salts. In some embodiments, examples of veterinary andagriculturally acceptable salts are organic acid addition salts formedwith organic acids including, but not limited to, maleate, dimaleate,fumarate, tosylate, methanesulfonate, acetate, citrate, malonate,tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, anda-glycerophosphate. Of course, other acceptable organic acids may beused.

Alkali metal (for example, sodium, potassium or lithium) or alkalineearth metal (for example calcium) salts of the compounds can also bemade by reacting a sufficiently acidic residue on the compounds with ahydroxide of the alkali metal or alkaline earth metal.

Veterinarily acceptable salts may be obtained using standard procedureswell known in the art, for example by reacting a sufficiently basiccompound such as an amine with a suitably acid functional group presentin the compound, or by reacting a suitable acid with a suitably basicfunctional group on the compound of the invention.

The compounds of Formula (1) may be prepared by processes adapted fromthose described in U.S. Pat. Nos. 5,514,773; 5,747,448; 5,874,530;5,856,436; 6,033,879; 5,763,221; 6,329,338, 5,116,815; 6,468,966;6,369,028; 5,777,075; and 5,646,244. In addition, various syntheticmethods for cyclic depsipeptides have been reported in the chemicalliterature (see Luttenberg et al., Tetrahedron 68 (2012), 2068-2073;Byung H. Lee, Tetrahedron Letters, 1997, 38 (5), 757-760; Scherkenbecket al., Eur. J Org. Chem., 2012, 1546-1553; Biosci. Biotech. Biochem.,1994, 58(6), 1193-1194; and Scherkenbeck et al., Tetrahedron, 1995,51(31), 8459-8470) It will be understood by those skilled in the artthat certain functional groups in the compounds and intermediates may beunprotected or protected by suitable protecting groups, as taught byGreene and Wuts, Protective Groups in Organic Synthesis, John Wiley andSons, Inc., 4th edition 2006. Further, it will be apparent to thoseskilled in the art that the compounds and intermediates may be isolatedby standard aqueous work-up conditions and optionally purified. Forexample, the compounds or intermediates may be purified bychromatographic methods or crystallized to yield the desired product insuitable purity.

One skilled in the art will recognize that, in some cases, after theintroduction of a given reagent as it is depicted in the schemes, it maybe necessary to perform additional routine synthetic Steps not describedin detail to complete the synthesis of Formula (1) compounds.

The present invention includes all veterinary acceptableisotopically-labelled Formula (1) compounds wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature. Examples of isotopes suitable for inclusion in thecompounds of the present invention include isotopes of hydrogen, such as²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, and sulphur, such as ³⁵S.

The skilled person will appreciate that the compounds of the presentinvention could be made by methods other than those herein described asincorporated herein by reference, by adaptation of the methods hereindescribed and/or adaptation of methods known in the art, for example theart described herein, or using standard textbooks such as “ComprehensiveOrganic Transformations—A Guide to Functional Group Transformations”, RC Larock, Wiley-VCH (1999 or later editions).

The Formula (1) compounds are useful as antiparasitic agents, therefore,another aspect of the present invention is a veterinary compositioncomprising a therapeutically effective amount of a Formula (1) compound,stereoisomers thereof, and at least one veterinary acceptable excipient.The compounds of the present invention (including the compositions andprocesses used therein) may also be used in the manufacture of amedicament for the therapeutic applications described herein.

The compound of the present invention can be administered alone or in aformulation appropriate to the specific use envisaged, the particularspecies of host animal being treated and the parasite involved.Generally, it will be administered as a formulation in association withat least one veterinary acceptable excipient. The term “excipient” isused herein to describe any ingredient (e.g., carrier, diluents, and thelike) other than the compound of the present invention or any additionalveterinary (e.g., antiparasitic) agent. The choice of excipient will toa large extent depend on factors such as the particular mode ofadministration, the effect of the excipient on solubility and stability,and the nature of the dosage form. In addition to the excipient(s), theamount of the compound of the present invention that is administered andthe dosage regimen for treating a condition or disorder with thecompound depends on a variety of factors, including the age, weight, sexand medical condition of the animal, the severity of the disease, theroute and frequency of administration, and thus may vary widely.

In another aspect, the veterinary composition comprises a Formula (1)compound with at least one veterinary acceptable excipient. Theconcentration range will vary depending on the composition (e.g., oral,topical, or injectable). For an oral dose, the range of active (i.e.,compound of the present invention) is about 0.1 to 50 mg/kg, preferablyfrom about 0.2 to 25 mg/kg, and even more preferably from about 0.25 to10 mg/kg, and most preferably from about 0.5 to 7 mg/kg or 1-5 mg/kg.For a topical solution, the range of active is about 0.1 to 1000 mg/mL,and preferably from about 0.5 to 500 mg/mL, and more preferably fromabout 1 to 250 mg/mL, and even more preferably from about 2 to 200mg/mL. Depending upon the final volumes of the topical solution(s), theconcentration of the active can change from that described above.Generally, injectable doses tend to be, but not always, lower inconcentration.

The formulations can be prepared using conventional dissolution andmixing procedures. Such compositions and methods for their preparationmay be found, for example, in ‘Remington's Veterinary Sciences’, 19thEdition (Mack Publishing Company, 1995; and “Veterinary Dosage Forms:Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y.,1980 (ISBN 0-8247-6918-X).

A typical formulation is prepared by mixing a Formula (1) compound withat least one veterinary acceptable excipient. Suitable excipients arewell known to those skilled in the art and include materials such ascarbohydrates, waxes, water soluble and/or swellable polymers, starches,hydrophilic or hydrophobic materials, gelatin, oils, solvents, water,and the like. The particular excipient(s) will depend upon the means andpurpose for which the compound of the present invention is beingapplied. Solvents are generally selected based on solvents recognized bypersons skilled in the art as safe to be administered to an animal. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, flavoring agents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or veterinary composition thereof) oraid in the manufacturing of the veterinary product (i.e., medicament).The compound of the present invention will typically be formulated intoveterinary dosage forms to provide an easily controllable dosage formfor administration.

The methods by which the compound of the present invention may beadministered include oral, topical, and injectable (e.g., parenteral andsubcutaneous) administration. The particular route selected by thepractitioner depends upon factors such as the physicochemical propertiesof the therapeutic agent, the condition of the host and economics. Incertain cases, it is convenient and efficient to administer veterinarymedicines orally by placing the therapeutic agent in a solid or liquidmatrix that is suitable for oral delivery. These methods includechewable drug-delivery formulations. The problem associated withadministering oral formulations to animals is that the therapeutic agentoften provides an unpleasant taste, aroma, or texture, which causes theanimals to reject the composition. This is further exacerbated bycompositions that are hard and difficult to swallow.

The compound of the present invention can be administered orally bycapsule, bolus, tablet, powders, lozenges, chews, multi andnanoparticulates, gels, solid solution, films, sprays, or liquid form.This is a preferred method of administration and as such it is desirableto develop the compound for oral administration. Such formulations maybe employed as fillers in soft or hard capsules, soft or hard palatablechews, which typically comprise at least one veterinary acceptableexcipient, for example, water, ethanol, polyethylene glycol,N-methylpyrrolidone, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents, flavorants, and/or suspendingagents. Liquid forms include suspensions, solutions, syrups, drenchesand elixirs. Liquid formulations may also be prepared by thereconstitution of a solid, for example, from a sachet. Oral drenches arecommonly prepared by dissolving or suspending the compound of thepresent invention in a suitable medium (e.g. triethylene glycol, benzylalcohol, and the like). The compound of the present invention can alsobe formulated with a food substance, e.g., a dietary admixture (foodpellets or powder for birds).

The compound of the present invention can be administered topically tothe skin or mucosa, that is dermally or transdermally. This is anotherpreferred method of administration and as such it is desirable todevelop the compound of the present invention to be suited to suchformulations, for example liquid forms. Typical formulations for thispurpose include pour-on, spot-on, multi-spot-on, stripe-on, comb-on,roll-on, dip, spray, mousse, shampoo, powder formulation, gels,hydrogels, lotions, solutions, creams, ointments, dusting powders,dressings, foams, films, skin patches, wafers, implants, sponges,fibers, bandages and micro emulsions. Liposomes may also be used.Typical excipients include alcohol, water, mineral oil, liquidpetrolatum, white petrolatum, glycerin, N-methyl formamide, glycolmonomethyl ethers, polyethylene glycol, propylene glycol, and the like.Penetration enhancers may be incorporated—see, for example, J Pharm Sci,88 (10), 955-958 by Finnin and Morgan (October 1999). Pour-on or spot-onformulations may be prepared by dissolving the active ingredients in anacceptable liquid excipient such as butyl digol, liquid paraffin or anon-volatile ester, optionally with the addition of a volatile componentsuch as propan-2-ol or a glycol ether. Alternatively, pour-on, spot-onor spray formulations can be prepared by encapsulation, to leave aresidue of active agent on the surface of the animal, this effect mayensure that the compound of the present invention has increasedpersistence of action and is more durable, for example it may be morewater-fast. Topical formulations contemplated herein can comprise fromabout 0.1 mg/kg to 50 mg/kg of a compound of the present invention, andmore preferably from about 1 mg/kg to 10 mg/kg of a compound of thepresent invention, and even more preferably, from 1 mg/kg to 5 mg/kg.

The compounds of the present invention can also be administeredtopically via a support matrix for example, a synthetic or naturalresin, plastic, cloth, leather, or other such polymeric system in theshape of a collar or ear tag. Said collar or ear tag may be coated,impregnated, layered, by any means so as to provide a veterinaryacceptable amount of a compound of the present invention alone, or withat least one veterinary acceptable excipient, and optionally anadditional antiparasitic agent, or veterinary acceptable salts thereof.Such formulations are prepared in a conventional manner in accordancewith standard medicinal or veterinary practice. Further, theseformulations will vary with regard to the weight of active compoundcontained therein, depending on the species of host animal to betreated, the severity and type of infection or infestation, and the bodyweight of the animal. The volume of the applied composition can be fromabout 0.2 mL/kg to 5 mL/kg and preferably from about 1 mL/kg to 3 mL/kg.

Agents may be added to the formulations of the present invention toimprove the persistence of such formulations on the surface of theanimal to which they are applied, for example to improve theirpersistence on the coat of the animal. It is particularly preferred toinclude such agents in a formulation which is to be applied as a pour-onor spot-on formulation. Examples of such agents include acryliccopolymers and in particular fluorinated acrylic copolymers. Aparticular suitable reagent is the trademark reagent “Foraperle”(Redline Products Inc, Texas, USA). Certain topical formulations mayinclude unpalatable additives to minimize oral exposure.

The compounds of the present invention can also be administered byinjection. Injectable (e.g., subcutaneous and parenteral) formulationsmay be prepared in the form of a sterile solution, which may containother substances, for example enough salts or glucose to make thesolution isotonic with blood. Acceptable liquid excipients includevegetable oils such as sesame oil, glycerides such as triacetin, esterssuch as benzyl benzoate, isopropyl myristate and fatty acid derivativesof propylene glycol, as well as organic solvents such aspyrrolidin-2-one and glycerol formal. The formulations are prepared bydissolving or suspending compounds of the present invention alone orwith at least one additional antiparasitic agent in the liquid excipientsuch that the final formulation contains from about 0.01 to 30% byweight of the active ingredients.

Suitable devices for injectable administration include needle (includingmicro needle) injectors, needle-free injectors and infusion techniques.Injectable formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dry powder form to be used in conjunction with a suitable vehicle suchas sterile, pyrogen-free water. The preparation of injectableformulations under sterile conditions, for example, by lyophilization,may readily be accomplished using standard veterinary techniques wellknown to those skilled in the art. The solubility of a compound of thepresent invention used in the preparation of an injectable solution maybe increased by the use of appropriate formulation techniques, such asthe incorporation of solubility-enhancing agents.

Administration of the compound of the instant invention is contemplatedto be once a month. However, an extended duration formulation may allowfor dosing once every 2, 3, 4, 5, or 6 months.

Such formulations are prepared in a conventional manner in accordancewith standard medicinal or veterinary practice. Further, theseformulations will vary with regard to the weight of active compoundcontained therein, depending on the species of host animal to betreated, the severity and type of infection or infestation, and the bodyweight of the animal.

The composition of the present invention may be administered alone, asdescribed above, or in combination with at least one other additionalantiparasitic agent to form a multi-component parasiticide giving aneven broader spectrum of veterinary utility. Thus, the present inventionalso envisions a combination veterinary composition comprising aneffective amount of the compound of the present invention in combinationwith at least one other additional antiparasitic agent and can furthercomprise at least one veterinary acceptable excipient.

The following list of additional antiparasitic agents together withwhich the compound of the present invention can be used is intended toillustrate the possible combinations, but not to impose any limitation.Non-limiting examples of additional antiparasitic agents include:amitraz, aminoacetonitriles, albendazole, cambendazole, fenbendazole,flubendazole, thiabendazole, mebendazole, cyclic octadepsipeptides,oxfendazole, oxibendazole, paraherquamide, parbendazole, piperazines,praziquantel, thiabendazole, tetramisole, triclabendazole, levamisole,pyrantel (including the salt forms—pamoate, citrate, and tartrate),oxantel, morantel, abamectin, doramectin, emamectin, eprinomectin,ivermectin, moxidectin, selamectin, dimadectin, latidectin, lepimectin,milbemycin, milbemycin oxime, demiditraz, emodepside, fipronil,methoprene, diethylcarbamazine, hydroprene, kinoprene, lufenuron,metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyfen,closantel, clorsulon, novaluron, fluazuron, spinosad, sarolaner((S)-1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)-ethan-1-one),fluralaner(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)-ethyl)benzamide),afoxolaner(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-1-naphthamide),lotilaner(3-methyl-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]thiophene-2-carboxamide);and mixtures thereof. Preferred additional antiparasitic agents includemoxidectin, doramectin, selamectin, abamectin, milbemycin, milbemycinoxime, pyrantel, praziquatel, and levamisole.

The veterinary composition for application to an animal may be packagedin a variety of ways depending upon the method used for administeringthe compound of the present invention or combination, thereof.Generally, an article for distribution includes a container havingdeposited therein the veterinary composition in an appropriate form.Suitable containers are well-known to those skilled in the art andinclude materials such as bottles (plastic and glass), sachets,ampoules, plastic bags, metal cylinders, and the like. The container mayalso include a tamper-proof assemblage to prevent indiscreet access tothe contents of the package. In addition, the container has depositedthereon a label that describes the contents of the container. The labelmay also include appropriate warnings.

The compounds of the present invention (including the compositions andprocesses used therein) may also be used in the manufacture of amedicament for the therapeutic applications described herein.

The compounds of the present invention, stereoisomers thereof, andcompositions comprising a therapeutically effective amount of a Formula(1) compound and at least one veterinary acceptable excipient are usefulas ectoparasiticides for the control and treatment of infections orinfestations manifested by said ectoparasite in an animal. The compoundsof the present invention have utility as an ectoparasiticide, inparticular, as an acaricide and insecticide. They may, in particular, beused in the fields of veterinary medicine, livestock husbandry and themaintenance of public health: against acarids, insects, and copepodswhich are parasitic upon vertebrates, particularly warm-bloodedvertebrates, including companion animals, livestock, and fowl andcold-blooded vertebrates like fish.

The compounds of the present invention are useful for the treatment ofparasitic worms categorized as cestodes (tapeworms), nematodes(roundworms) and trematodes (flatworms or flukes). The gastrointestinalroundworms include, for example, Ostertagia ostertagi (includinginhibited larvae), O. lyrata, Haemonchus placei, H. similis, H.contortus, Toxocara canis, T. leonina, T. cati, Trichostrongylus axei,T. colubriformis, T. longispicularis, Cooperia oncophora, C. pectinata,C. punctata, C. surnabada (syn. mcmasteri), C. spatula, Ascaris suum,Hyostrongylus rubidus, Bunostomum phlebotomum, Capillaria bovis, B.trigonocephalum, Strongyloides papillosus, S. ransomi, Oesophagostomumradiatum, O. dentatum, O. columbianum, O. quadrispinulatum, Trichurisspp., and the like. Other parasites include: hookworms (e.g.,Ancylostoma caninum, A. tubaeforme, A. braziliense, Uncinariastenocephala); lungworms (e.g., Dictyocaulus viviparus andMetastrongylus spp); eyeworms (e.g., Thelazia spp.); parasitic stagegrubs (e.g., Hypoderma bovis, H. lineatum, Dermatobia hominis);kidneyworms (e.g., Stephanurus dentatus); screw worm (e.g., Cochliomyiahominivorax (larvae); filarial nematodes of the super-family Filarioideaand the Onchocercidae Family. Non-limiting examples of filarialnematodes within the Onchocercidae Family include the genus Brugia spp.(i.e., B. malayi, B. pahangi, B. timori, and the like), Wuchereria spp.(i.e., W. bancrofti, and the like), Dirofilaria spp. (D. immitis, D.repens, D. ursi, D. tenuis, D. spectans, D. lutrae, and the like),Dipetalonema spp. (i.e., D. reconditum, D. repens, and the like),Onchocerca spp. (i.e., O. gibsoni, O. gutturosa, O. volvulus, and thelike), Elaeophora spp. (E. bohmi, E. elaphi, E. poeli, E. sagitta, E.schneideri, and the like), Mansonella spp. (i.e., M. ozzardi, M.perstans, and the like), and Loa spp. (i.e., L. loa). In another aspectof the invention, the compound of the present invention is useful fortreating endoparasiticidal infection from filarial nematodes within thegenus Dirofilaria (i.e., D. immitis, D. repens, D. ursi, D. tenuis, andthe like).

The compounds of the present invention can also be used againstectoparasites, alone or in combination with at least one additionalantiparasitic agent. Some non-limiting examples of ectoparasitesinclude: ticks (e.g., Ixodes spp., (e.g., I. ricinus, I. hexagonus),Rhipicephalus spp., (e.g., R. sanguineus), Boophilus spp., Amblyommaspp. (e.g., A. maculatum, A. triste, A. parvum, A. cajennense, A. ovale,A. oblongoguttatum, A. aureolatum, A. cajennense), Hyalomma spp.,Haemaphysalis spp., Dermacentor spp. (e.g., D. variabilis, D. andersoni,D. marginatus), Ornithodorus spp., and the like); mites (e.g.,Dermanyssus spp., Sarcoptes spp., (e.g., S. scabiei), Psoroptes spp.,(e.g., P. bovis), Otodectes spp., Chorioptes spp., Demodex spp., (e.g.,D. folliculorum, D. canis, and D. brevis) and the like); chewing andsucking lice (e.g., Damalinia spp., Linognathus spp., Cheyletiella spp.,Haematopinus spp., Solenoptes spp., Trichodectes spp., Felicola spp.,and the like); fleas (e.g., Siphonaptera spp., Ctenocephalides spp., andthe like); biting flies, midges, and mosquitos (e.g., Tabanidae spp.,Haematobia spp., Musca spp., Stomoxys spp., Dematobia spp., Cochliomyiaspp., Simuliidae spp., Ceratopogonidae spp., Psychodidae spp., Aedesspp., Culex spp., Anopheles spp., and the like); bed bugs (e.g., insectswithin the genus Cimex and family Cimicidae); and grubs (e.g., Hypodermabovis, H. lineatum); and copepods (e.g., sea lice within the OrderSiphonostomatoida, including genera Lepeophtheirus and Caligus).

The compounds of the present invention and compositions comprisingcompounds of the present invention in conjunction with at least oneother antiparasitic agent are of particular value in the control ofectoparasites and endoparasites which are injurious to, or spread or actas vectors of diseases in companion animals, livestock, birds, and fish.The ectoparasites and endoparasites which can be treated with acombination of a Formula (1) compound and an additional antiparasiticagent include those as herein before described.

Any of the compounds of the present invention, or a suitable combinationof a compound of the present invention and optionally, with at least oneadditional antiparasitic agent may be administered directly to theanimal and/or indirectly by applying it to the local environment inwhich the animal dwells (such as bedding, enclosures, and the like).Direct administration includes contacting the skin, fur, or feathers ofa subject animal with the compound(s), or by feeding or injecting thecompounds into the animal.

The Formula (1) compound, stereoisomers thereof, veterinary acceptablesalts thereof, and combinations with at least one additionalantiparasitic agent, as described herein, are of value for the treatmentand control of the various lifecycle stages of parasites including egg,nymph, larvae, juvenile and adult stages.

The present invention also relates to a method of administering acompound of the present invention alone or in combination with at leastone additional antiparasitic agent, and optionally at least oneveterinary acceptable excipient, to animals in good health comprisingthe application to said animal to reduce or eliminate the potential forhuman parasitic infection or infestation from parasites carried by theanimal and to improve the environment in which the animals inhabit.

The present invention also relates to a method of administering acompound of the present invention alone or in combination with at leastone additional antiparasitic agent, and optionally at least oneveterinary acceptable excipient, to a human in good or poor healthcomprising the application to said human to reduce or eliminate thepotential for human parasitic infection or infestation from parasitescarried by the human and to improve the environment in which the humaninhabits.

The present invention also relates to a method of administering acompound of the present invention alone or in combination with at leastone additional antiparasitic agent, and optionally at least oneveterinary acceptable excipient, to a plant or soil to prevent parasiticinfection to the plant.

The reactions set forth below were done generally under a positivepressure of argon or nitrogen or with a drying tube, at ambienttemperature (unless otherwise stated), in anhydrous solvents, and thereaction flasks can be fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. Analytical thin layer chromatography (TLC) was performedusing glass-backed silica gel 60 F 254 precoated plates and eluted withappropriate solvent ratios (v/v). Reactions were assayed by TLC or LCMSand terminated as judged by the consumption of starting material.Visualization of the TLC plates was done with UV light (254 nMwavelength) or with an appropriate TLC visualizing solvent and activatedwith heat. Flash column chromatography (Still et al., J. Org. Chem. 43,2923, (1978) was performed using silica gel (RediSep Rf) or various MPLCsystems, such as Biotage or ISCO purification system.

Conventional methods and/or techniques of separation and purificationknown to one of ordinary skill in the art can be used to isolate thecompounds of the present invention, as well as the various intermediatesrelated thereto. Such techniques will be well-known to one of ordinaryskill in the art and may include, for example, all types ofchromatography (e.g., high pressure liquid chromatography (HPLC), columnchromatography using common adsorbents such as silica gel, andthin-layer chromatography (TLC), recrystallization, and differential(i.e., liquid-liquid) extraction techniques.

The compound structures in the examples below were confirmed by one ormore of the following methods: proton magnetic resonance spectroscopy,and mass spectroscopy. Proton magnetic resonance (1H NMR) spectra weredetermined using a Bruker spectrometer operating at a field strength of400 megahertz (MHz). Chemical shifts are reported in parts per million(ppm) downfield from an internal tetramethylsilane standard. Massspectra (MS) data were obtained using Agilent mass spectrometer withatmospheric pressure chemical ionization. Method: Acquity UPLC withchromatography performed on a Waters BEH C18 column (2.1×50 mm, 1.7 μm)at 50° C. The mobile phase was a binary gradient of acetonitrile(containing 0.1% trifluoroacetic acid) and water (5-100%).

Certain aspects of the present invention are illustrated by thefollowing Examples. It is to be understood, however, that the aspects ofthe invention are not limited to the specific details of these Examples,as other variations thereof will be known, or apparent in light of theinstant disclosure, to one of ordinary skill in the art.

Compounds of this invention can exist as one or more stereoisomers. Oneskilled in the art will appreciate that one stereoisomer may be moreactive and/or may exhibit beneficial effects when enriched relative tothe other stereoisomer(s) or when separated from the otherstereoisomer(s). Additionally, the skilled artisan knows how toseparate, enrich, and/or to selectively prepare said stereoisomers. Thecompounds of the invention may be present as a mixture of stereoisomers.

In the Schemes and Examples described below, the followingcatalysts/reactants and miscellaneous abbreviations include: roomtemperature (RT, or rt); dichloromethane (DCM); methanol (MeOH), ethanol(EtOH); tetrahydrofuran (THF); 4-dimethylaminopyridine (DMAP);t-butyloxycarbonyl (BOC, boc); palladium (Pd); palladium on carbon(Pd/C); N,N-diisopropylethylamine (DIPEA);1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); methoxymethylchloride (MOM-Cl); methoxy methyl bromide (MOM-Br); protecting group(Pg); saturated aqueous (Sat Aq); dimethyl formamide, sulfuric acid(H₂SO₄); iron (Fe); ethyl acetate (EtOAc); water (H₂O); ammoniumchloride (NH₄Cl); triethylamine (TEA; NEt₃); dimethyl formamide (DMF);dimethylsulfoxide (DMSO); hydrochloric acid (HCl); sodium hydroxide(NaOH); acetonitrile (CH₃CN); hydrogen peroxide (H₂O₂); trifluoroaceticacid TFA); benzyl bromide (BnBr); cesium carbonate (Cs₂CO₃); methyliodide (MeI); sodium hydride (NaH); sodium nitrite (NaNO₂); sodiumcarbonate (Na₂CO₃); magnesium sulfate (MgSO₄); denatured alcohol (IMS);1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC); N-methyl morpholine(NMM); hydrogen (H₂-gas); triphenylphosphine (PPh₃); Tri-Cl (tritylchloride); di-tert-butyl-azodicarboxylate (DBAD); propylphosphonicanhydride (T3P); hydrogen bromide (HBr); acetic acid (AcOH); copperiodide (CuI); sodium borohydride (NaBH₄); thionyl chloride (SOCl₂);potassium carbonate (K₂CO₃); acetic anhydride (Ac₂O); lithium aluminumhydride (LiAlH); sodium ethoxide (NaOEt); nitric acid (HNO₃); sodiumsulfate (Na₂SO₄); dimethoxy ethane (DME); tetrahydropyran (THP); zincdicyanide (Zn(CN)₂); aluminum chloride (AlCl₃); para-toluenesulfonicacid (PTSA);1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU);[1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂); zinc chloride (ZnCl₂); potassium bicarbonate (KHCO₃);sodium bicarbonate (NaHCO₃); isopropyl magnesium chloride·lithiumchloride (iPrMgCl—LiCl); diethyl azodicarboxylate (DEAD); thiaminepyrophosphate (TPP); pyridine (Py); lithium tert-butoxide (t-BuOli);di-tertbutyl decarbonate ((Boc)₂O);1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6); palladium hydroxideon carbon (H₂Pd(OH)₂); octyl 3-chloropropanoate (HIS(octyl)₃);tetrakis(triphenylphosphine)palladium (O) (Pd(PPh₃)₄; Pd(TPP)₄); andbis(triphenylphosphine)palladium(II) dichloride (PdCl₂(PPh₃)₂).

EXAMPLES PF1022A:(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-dibenzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone

Emodepside:(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-morpholinobenzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone

The following examples were prepared according to the Schemes andpreparations as presented herein.

(Intermediate Schemes 1a-1r)—Preparation of Monomers

In Scheme 1a, synthesis of monomers M1, M2, M3 and M4 was carried out byprocedures well known in the literature. (Journal of Organic Chemistry,79(17), 8491-8497; 2014; Organic Letters, 15(24), 6132-6135; 2013;ChemBioChem, 9(8), 1235-1242; 2008) These monomers were used in astepwise synthesis of the PF1022a core as shown in subsequent schemes.In addition, the allyl protected monomers, allyl (S)-2-hydroxypropanoateand allyl (R)-2-hydroxy-3-(4-nitrophenyl)propanoate and allyl(R)-2-hydroxy-3-phenylpropanoate were also prepared according to thefollowing literature procedures: Faming Zhuanli Shenqing, 101962323, 2Feb. 2011 and Journal of Organic Chemistry, 67(4), 1061-1070; 2002).These allyl protected monomers were used in an alternative route whichalso provided Bis-Iodo PF1022a using the same coupling conditionsdescribed below and the requisite chemistry to remove the allylprotecting group as described in T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

Synthesis of Boc-Methyl-L-Leucine (M1)

Sodium hydride (65.16 g, 1.63 mol) was added portion-wise over 1.25hours to a mixture of Boc-L-leucine (125 g, 0.50 mol) and iodomethane(160 mL, 2.50 mol) in THF (2 L) cooled to 0° C. The temperature wasmaintained below 5° C. during the addition and then allowed to warm upto room temperature and stirred for 2.5 days. The reaction mixture wascooled to 0° C. and quenched with water (2 L); the temperature wasmaintained below 5° C. during the addition and then allowed to warm upto room temperature. The aqueous layer was extracted with EtOAc (2×750mL), then the aqueous was acidified to pH 5 with 10% aqueous citric acidsolution, extracted with EtOAc (3×1 L), dried over MgSO₄, filtered andthe solvent removed in vacuo (50° C.) and azeotroped with DCM. The twobatches were combined to yield 236.09 g, 94% yield. ¹H NMR (CDCl₃, 300MHz): δ 4.85 (t, 0.5H), 4.61 (dd, 0.5H), 2.81 (s, 1.5H), 2.78 (s, 1.5H),1.77-1.65 (m, 2H), 1.57-1.51 (m, 1H), 1.45 (s, 9H), 0.95-0.92 (m, 6H).Chiral analysis: 99.5% e.e. by GC.

Synthesis of Benzyl-L-Lactate (M2)

L-Lactic acid (467 g, 5.2 mol, anhydrous) was dissolved in DMF (1 L).Cesium carbonate (847 g, 2.6 mol, 0.5 eq) was added with stirring,followed by benzyl bromide (886 g, 5.18 mol, 0.99 eq) over about 45minutes. The mixture was stirred at room temperature for 4 days, afterwhich time analysis showed the reaction to be complete. Heteroneousmixture was filtered through Celite®; the filter cake was washed withethyl acetate (2×500 mL). The filtrate was extracted with water (2×500mL), saturated aqueous Na₂CO₃ (4×500 mL) and brine (2×500 mL), thenconcentrated in vacuo to yield a thick orange oil, 775 g, 80%. This waspurified by dry flash chromatography using EtOAc/heptane (0% to 10%) aseluent. Appropriate fractions were combined and concentrated in vacuo toyield benzyl-L-lactate, 385 g, 41%. ¹H NMR (CDCl₃, 300 MHz): δ 7.40-7.35(m, 5H), 5.21 (s, 2H), 4.37-4.27 (m, 1H), 2.79 (d, 1H), 1.43 (d, 3H).

Synthesis of benzyl(R)-2-hydroxy-3-(4-((methoxycarbonyl)amino)phenyl)propanoate (M3)

Step 1:

NaNO₂ (147.6 g, 2.13 mol) in water (600 mL) was added drop-wise to amixture of 4-nitro-D-phenylalanine, (150 g, 0.71 mol) in 1M H₂SO₄(aqueous, 900 mL), water (750 mL) and acetone (2.25 L) maintaining atemperature between −5° C. and −3° C. The mixture was stirred at −5° C.for 1.5 hours then allowed to warm to room temperature and stirred for 3days. The mixture was concentrated in vacuo to remove the acetone andthe mixture was extracted with EtOAc (5×˜375 mL), the combined organicswere dried over MgSO₄ filtered and the solvent removed in vacuo to yielda yellow solid that was recrystallised from isopropyl acetate (˜2.5volumes), to yield p-nitrophenyl-D-lactic acid (68.38 g, 45%) as ayellow solid; a second crop 6.25 g (combined yield 50%) was obtainedfrom the residue by slurrying in DCM. ¹H NMR (CDCl₃, 300 MHz): δ 8.18(d, 2H), 7.45 (d, 2H), 4.59-4.54 (m, 1H), 3.31 (dd, 1H), 3.10 (dd, 1H).No chiral analysis was performed.

Step 2:

Cs₂CO₃ (123.3 g, 378 mmol) was added to a mixture ofp-nitrophenyl-d-lactic acid (156.75 g, 742 mmol) in DMF (700 mL) andstirred for 15 minutes, gas was evolved and the heterogenous solutioncleared yielding a homogenous brown solution (a mild exotherm wasobserved). Benzyl bromide (124.39 g, 727 mmol) in DMF (140 mL) was addedat room temperature over about 5 minutes; a precipitate formed and themixture was stirred for about 20 hours at room temperature. The mixturewas filtered through Celite® and the filter cake was washed with EtOAc(2×500 mL), the filtrate was washed with water (2×500 mL), saturatedaqueous NaHCO₃ (3×500 mL), and then brine (500 mL). Heptane (about 1 L)was added to the organic layer and the resultant off white precipitatewas filtered off, further crops were obtained from the mother liquorsafter concentration and trituration with heptanes. The batches weredried at 40° C. for about 18 hours and combined to yield an off whitesolid (197.6 g, 88% yield). ¹H NMR (CDCl₃, 300 MHz): δ 8.04 (m, 2H),7.45-7.25 (m, 7H), 5.20 (dd, 2H), 4.55-4.48 (m, 1H), 3.25-3.00 (dd, 2H),2.86 (d, 1H). UPLC (CSH_C18, Short acid 2-95%): 0.73 minutes; no massion observed.

Step 3:

Iron powder (256 g, 4.59 mol) was added to a stirred mixture of(R)-benzyl 2-hydroxy-3-(4-nitrophenyl)propanoate (197.5 g, 0.66 mol),ammonium chloride (455 g, 8.52 mol), EtOAc (1 L), water (900 mL), IMS(100 mL) heated at 60° C. The reaction became darker in colour and wasstirred for 18 hours at 50° C. The mixture was cooled, filtered throughCelite® and the filter cake was washed with EtOAc (about 600 mL). Thelayers were separated, and the organic layer was washed with water(3×500 mL). The organic layer was extracted with aqueous 1 M HCl (4×250mL); then the acidic extracts were basified with saturated aqueousNaHCO₃ until about pH 8-9. This was extracted into EtOAc (1 L, then2×500 mL); the combined organic layers were concentrated in vacuo toyield a solid which was azeotroped with toluene, EtOAc, then DCM. Theresidue was dried at 50° C. to yield an off white solid (146.5 g, 82%).¹H NMR (CDCl₃, 300 MHz): δ 7.42-7.30 (m, 5H), 6.91 (d, 2H), 6.56 (d,2H), 5.13 (s, 2H), 4.42 (t, 1H), 3.54 (s, br 1H), 3.08-2.80 (m, 2H).UPLC (CSH_C18, Short acid 2-95%): 0.32 min, 271.43 Da [M+H]⁺.

Step 4:

Methyl chloroformate (24.5 mL, 316 mmol, 1.5 eq.), was added drop-wiseto a stirred mixture of (R)-benzyl 3-(4-aminophenyl)-2-hydroxypropanoate(57.30 g, 211 mmol), EtOAc (375 mL) and saturated aqueous NaHCO₃ (300mL, 5.2 vol) at room temperature over about 20 minutes (a mild exothermto about 25° C. was observed along with gas evolution). The mixture wasstirred for a further 10 minutes, the organic layer was removed andwashed with brine (200 mL), dried over Na₂SO₄ filtered and concentratedin vacuo to yield M3 as a white solid (73.48 g, 99% yield)¹H NMR (CDCl₃,300 MHz): δ 7.42-7.31 (m, 5H), 7.26-7.13 (m, 2H), 7.12-7.01 (m, 2H),6.70 (s, 1H), 5.13-5.22 (m, 2H), 4.49-4.43 (m, 1H), 3.74 (s, 3H), 3.06(dd, 1H), 2.93 (dd, 1H), 2.82 (d, 1H). UPLC (CSH_C18, Short acid 2-95%):0.64 min, 330.4 Da [M+H]⁺.

Synthesis of benzyl (R)-2-hydroxy-3-phenylpropanoate (M4)

Cs₂CO₃ (97.5, 300 mmol) was added to a mixture of(R)-2-hydroxy-3-phenylpropanoic acid (100 g, 602 mmol) in DMF (700 mL)and stirred for 15 minutes, gas was evolved and the heterogenoussolution cleared yielding a homogenous brown solution (a mild exothermwas observed). Benzyl bromide (102.0 g, 602 mmol) in DMF (100 mL) wasadded at room temperature over about 5 minutes; a precipitate formed andthe mixture was stirred for about 20 hours at room temperature. Themixture was filtered through Celite® and the filter cake was washed withEtOAc (2×400 mL), the filtrate was washed with water (2×400 mL),saturated aqueous NaHCO₃ (3×400 mL), and then brine (300 mL). Heptane(about 1 L) was added to the organic layer and the resultant off whiteprecipitate was filtered off, further crops were obtained from themother liquors after concentration and trituration with heptanes. Thebatches were dried at 40° C. for about 18 hours and combined to yield anoff white solid (M4, 151 g, 89% yield). ¹H NMR (CDCl₃, 300 MHz): δ 8.04(m, 2H), 7.45-7.25 (m, 7H), 5.20 (dd, 2H), 4.55-4.48 (m, 1H), 3.25-3.00(dd, 2H), 2.86 (d, 1H).

As shown in Scheme 1 b, dimers D1 and D2 are prepared using standardamide bond forming methods and ester bond forming methods followed bystandard protecting group removal steps. Tetramer T1, is formed from thereaction of D1 with D2 using routine amide bond forming methods. T1 isthen selectively deprotected to provide either of two tetramers, T1-1and T1-2, which when coupled together provide the corresponding linearoctadepsipeptide, O1. Sequential deprotection and cyclization yieldedthe appropriately aryl functionalized cyclic octadepsipeptide, C1.Conversion to the advanced intermediate Bis-Iodo PF1022a wasaccomplished by performing a two-step sequence that included protectinggroup removal followed by routine sequence to convert the amino group toan iodo group. It will be appreciated by ones skilled in the art thatmono-Iodo PF1022a may be readily obtained from the route shown in Scheme1b through the appropriate use of M3 and M4.

Synthesis of(R)-1-(benzyloxy)-3-(4-((methoxycarbonyl)amino)phenyl)-1-oxopropan-2-ylN-(tert-butoxycarbonyl)-N-methyl-L-leucinate (D1)

Step 1:

EDC·HCl (134.8 g, 703 mmol), was added in one portion to a mixture of(R)-benzyl 2-hydroxy-3-(4-((methoxycarbonyl)amino)phenyl)propanoate(178.2 g, 541 mmol), Boc-Methyl-L-Leucine (146.0 g, 595 mmol), DMAP(6.60 g, 54 mmol), 4-methylmorpholine (154.6 mL, 406 mmol) and DCM (3.4L). EDC·HCl slowly dissolves forming an orange solution; a mild exothermwas controlled by cooling after about 15 minutes. After 5 hours thereaction was washed with water (2×2 L), 10% aqueous citric acid solution(2×1 L), 5% aqueous citric acid solution (1×1 L), saturated aqueousNaHCO₃, water (1 L), dried over MgSO₄, filtered and the solvent removedin vacuo to yield an oil 296.1 g, 98%. ¹H NMR (CDCl₃, 400 MHz): δ7.44-6.95 (m, 9H), 6.67-6.45 (m, 1H), 5.36-4.64 (m, 4H), 4.14-3.63 (m,3H), 3.22-2.92 (m, 2H), 2.74-2.50 (m, 3H), 1.69-1.32 (m, 12H), 1.01-0.79(m, 6H). UPLC (CSH_C18, Short acid, 2-95%): 1.06 min, 457.6 Da,[M-Boc+H]⁺.

Step 2:

Pd—C 10% w/w (20.7 g, 19 mmol) was washed into a solution of(R)-1-(benzyloxy)-3-(4-((methoxycarbonyl)amino)phenyl)-1-oxopropan-2-ylN-(tert-butoxycarbonyl)-N-methyl-L-leucinate (296 g, 532 mmol) inindustrial methylated spirits (IMS, 3 L) with toluene (about 80 mL). Themixture was left to stir for about 18 hours under hydrogen (1 atm) for 2days. The mixture filtered through Celite®, the filter cake was washedwith IMS (about 500 mL) and the mixture concentrated in vacuo. Theresidue was purified by filtering through a plug of silica eluting with40% EtOAc in heptanes and concentrated in vacuo to yield D1. (232.72 g,91%). ¹H NMR (CDCl₃, 300 MHz): δ 7.35-7.25 (m, 2H), 7.17-7.11 (m, 2H),6.94 (s, br 1H), 5.27-5.18 (m, 1H), 4.73-4.67 (m, 1H), 3.76 (s, 3H),3.20-3.05 (m, 2H), 2.80-2.70 (m, 3H), 1.76-1.40 (m, 11H), 0.95-0.85 (M,6H), 96.72% pure w/w by HNMR with 0.34% DCM and 1.60% EtOAc, equivalentto 225.08 g, 90.6%. UPLC (CSH_C18, Short acid 2-95%): 0.86 min, 367.6 Da[M-Boc+H]⁺.

Synthesis of Synthesis of (R)-1-(benzyloxy)-1-oxopropan-2-ylN-(tert-butoxycarbonyl)-N-methyl-L-leucinate (D2)

Step 1:

Triphenylphosphine (192 g, 732 mmol), Boc-Methyl-L-Leucine (165 g, 672.6mmol), and benzyl-L-Lactate (120 g, 666 mmol) were dissolved intetrahydrofuran (700 mL). The resulting solution was cooled to 0° C.,then di-tertbutylazodicarboxylate (192 g, 834 mmol, 1.25 eq.) was addedportionwise, maintaining internal temperature<5° C. Once additioncomplete, mixture was allowed to stir and warm to room temperatureovernight, during which time an off-white precipitate had formed.Heptane (500 mL) was added, and the resulting mixture filtered throughCelite®. The cake was washed with heptane (2×100 mL). The filtrate wasconcentrated in vacuo to yield a thick orange oil (602 g). Heptane (500mL) was added, and the mixture was stirred vigorously for about 1 hour,resulting in further white precipitate forming. This was removed byfiltration; the cake was washed with heptane (2×300 mL). The resultingfiltrate was loaded directly onto silica (2 kg), and eluted withEtOAc/hetane (1% to 10%). First fraction (72.6 g) still containedtriphenylphosphine oxide; this was recolumned (about 700 g silica, about10% loading), using EtOAc/heptane (0% to 6%), to yield 68.2 g (25.1%) ofBoc-MeLeu-DLac-OBn. The second fraction from the initial column wasconcentrated in vacuo to yield 100.1 g (combined=168.3 g, 62%) of(R)-1-(benzyloxy)-1-oxopropan-2-ylN-(tert-butoxycarbonyl)-N-methyl-L-leucinate as a straw coloured oil. ¹HNMR (CDCl₃): δ 7.46-7.30 (m, 5H), 5.21-5.08 (m, 3H), 4.99-4.70 (ddd,1H), 2.73 (d, 3H), 1.73-1.40 (m, 18H), 0.92 (t, 6H). UPLC (CSH_C18,Short acid 2-95%): 1.08 min, 308.5 Da [M-Boc+H]⁺.

Step 2:

(R)-1-(benzyloxy)-1-oxopropan-2-ylN-(tert-butoxycarbonyl)-N-methyl-L-leucinate (100.1 g, 243 mmol) wasdissolved in dichloromethane (575 mL, 5.75 vol), and subsequently cooledto 0° C. Trifluoroacetic acid (150 mL, 1.96 mol, 8 eq., 1.5 vol) wasthen introduced. UPLC data after 4 hours indicated that reaction wasabout 50% complete. Further portion of trifluoroacetic acid (75 mL, 980mmol, 4 eq., 0.75 vol) was added. UPLC indicated not complete after 7hours, so mixture was stirred overnight for about 16 hours. Toluene (300mL) was added, and the mixture concentrated in vacuo to yield a thickorange oil, (D2)¹H NMR shows residual toluene and trifluoroacetic acid.¹H NMR (CDCl₃, 300 Mhz): 9.67-9.15 (br s, 1H), 8.65-8.10 (br s, 1H),7.47-7.26 (m, 5H), 5.29-5.09 (m, 3H), 3.97-3.85 (m, 1H), 1.92-1.78 (m,1H), 1.77-1.66 (m, 2H), 1.59-1.54 (s, 3H), 0.98-0.90 (m, 6H). UPLC(CSH_C18, Short acid 2-95%): 0.43 min, 308.5 Da [M+H]⁺.

Synthesis of (R)-1-(benzyloxy)-1-oxopropan-2-ylN—((R)-2-((N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)oxy)-3-(4-((methoxycarbonyl)amino)phenyl)propanoyl)-N-methyl-L-leucinate(T1)

D1 (193 g, 458 mmol) and D2 (225 g, 482 mmol) were stirred indichloromethane (2 L). HATU (250 g, 658 mmol, 1.36 eq.) was added,followed by diisopropylethylamine (375 mL, 2150 mmol) through a droppingfunnel. Temperature of reaction was maintained with the use of anexternal ice-bath. The mixture was allowed to stir overnight at roomtemperature. The reaction mixture was washed with water (3×2 L), aqueouscitric acid (10%, 2×1 L), saturated aqueous NaHCO₃ (2×1 L), and water (1L). The organic phase was dried over MgSO₄, filtered and concentrated invacuo to yield an orange oil. This was purified by dry flashchromatography using EtOAc/heptane as eluent (0% to 30%), to yield T1(313 g, 83%).

¹H NMR (CDCl₃, 300 MHz): δ 7.41-7.26 (m, 7H), 7.20-7.10 (m, 2H), 6.59(s, 1H), 5.42-4.60 (m, 6H), 3.82-3.71 (m, 3H), 3.10-2.96 (m, 2H),2.93-2.71 (m, 6H), 1.77-1.36 (m, 18H), 1.01-0.83 (m, 12H). UPLC(CSH_C18, Short acid, 2-95%): 1.14 min, 656.9 Da [M-Boc+H]⁺.

Synthesis of (R)-1-(benzyloxy)-1-oxopropan-2-ylN—((R)-3-(4-((methoxycarbonyl)amino)phenyl)-2-((methyl-L-leucyl)oxy)propanoyl)-N-methyl-L-leucinate(T1-1)

T1 (48.7 g, 64.4 mmol) was dissolved in dichloromethane (300 mL, 6 vol).The resulting solution was cooled to 0° C. with an external ice-bath.Trifluoroacetic acid (75 mL, 980 mmol, 1.5 vol) was added to thereaction mixture and the mixture stirred until complete. Toluene (300mL) was added, and the mixture concentrated in vacuo yield a thickorange oil, 65.3 g, about 125% (cont ˜16 g of trifluoroacetic acid).Used without further purification. ¹H NMR (CDCl₃, 300 MHz): δ 7.40-7.23(m, 9H), 6.73 (s, 1H), 5.50-5.42 (m, 1H), 5.29-5.08 (m, 4H), 3.87-3.83(m, 1H), 3.79-3.77 (m, 3H), 3.06 (d, 2H), 3.01-2.90 (m, 3H), 2.70-2.64(m, 3H), 2.36 (m, 3H), 1.76-1.42 (m, 6H), 1.39-1.25 (m, 2H), 1.04-0.96(m, 1H), 0.94-0.87 (m, 6H), 0.79-0.76 (m, 6H). UPLC (CSH_C18, Short acid2-95%): 0.65 min, 656.91 Da [M+H]⁺.

Synthesis of(65,9R,12S,15R)-6,12-diisobutyl-9-(4-((methoxycarbonyl)amino)-benzyl)-2,2,5,11,15-pentamethyl-4,7,10,13-tetraoxo-3,8,14-trioxa-5,11-diazahexadecan-16-oicacid (T1-2)

Pd—C (10% w/w, 2.5 g, 2.3 mmol) was washed into a solution of T1 (48.3g, 63.9 mmol) in IMS (500 mL) with toluene (about 20 mL) and stirredunder hydrogen (1 atm) for 4 hours, filtered and the solvent removed invacuo and then azeotroped with DCM to yieldBoc-MeLeu-DCbmPheLac-MeLeu-DLac-OH as an off-white foam 48.87 g, 115%yield (used crude in subsequent reaction). ¹H NMR (CDCl₃, 400 MHz): δ7.05-7.29 (m, 4H), 5.70 (t, 1H), 4.65-5.45 (m, 5H), 3.75 (d, 3H),2.68-3.19 (m, 8H), 2.30-2.34 (m, 1H), 1.38-1.74 (m, 17H), 1.10-1.29 (m,1H), 0.83-0.99 (m, 13H). UPLC (CSH_C18, Short acid 2-95%): 0.97 min,610.8 Da [M-tBu+H]⁺, 664.8 Da [M−H]⁻.

Synthesis of dimethyl((((2S,5R,8S,11R,14S,17R,20S,23R)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))dicarbamate(C1)

Step 1:

T1-1 (49.3 g, actual mass 65.3 g, contains ˜16 g trifluoroacetic acid,64.4 mmol) and T1-2 (42.5 g, actual mass 48.5 g, contains residualsolvent from hydrogenation) were dissolved in dichloromethane (500 mL).The mixture was cooled with an external ice-bath. HATU (36.4 g, 95.7mmol, 1.5 eq.) was added, followed by diisopropylethylamine (70 mL, 400mmol, 6.3 eq.). The resulting mixture was stirred for 20 hours. Water (1L) was added to the reaction mixture, and vigorously stirred for 0.83hours. The layers were separated, and the organic phase washed with aq.citric acid (10%, 3×700 mL), saturated aqueous NaHCO₃ (1×700 mL), andbrine (1×500 mL), then dried over MgSO₄, filtered and concentrated invacuo directly onto Celite® (150 g) and silica gel (20 g). The materialwas dry loaded onto a column of silica (1 kg) and purified by dry flashchromatography using EtOAc/heptane (0-50%) as eluent. This afforded,after concentration in vacuo, O1, 85 g, 101% (some trace heptaneobservable in ¹H NMR spectrum). ¹H NMR (CDCl₃, 300 MHz): δ 7.06-7.34 (m,13H), 6.61 (s, 1H), 4.58-5.46 (m, 10H), 3.73-3.76 (m, 6H), 2.66-3.16 (m,15H), 1.16-1.69 (m, 28H), 0.83-0.98 (m, 24H). UPLC (CSH_C18, Long acid,2-95%): RT 3.53 min, 1204.5 Da, [M-Boc+H]⁺.

Step 2:

O1 (199.5 g, 153 mmol) was dissolved in IMS (400 mL, 2 vol) and chargedto the 2 L autoclave. 5% Pd/C (2 g) was added as a paste in toluene. Theautoclave was sealed and charged to 150 psi hydrogen pressure. Afterstirring for 5 h at RT, 16% starting material remained so the autoclavewas recharged to 150 psi and allowed to stir at RT overnight. Thereaction was complete by UPLC, so the autoclave was vented and thecatalyst removed by filtration through Whatman GF/A media, washing withIMS (50 mL) and ethyl acetate (200 mL). The solvent was removed on therotary to leave a white foam, 01-1 (175 g, 94% yield). ¹H NMR (CDCl₃,300 MHz): δ 7.06-7.34 (m, 8H), 4.58-5.46 (m, 10H), 3.73-3.76 (m, 6H),2.66-3.16 (m, 15H), 1.16-1.69 (m, 28H), 0.83-0.98 (m, 24H). UPLC (Longacid, 2-95%): RT 3.36 min, 1113.5 Da, [M-Boc+H]⁺.

Step 3:

O1-1 (245 g, 202 mmol) was dissolved in DCM (1.5 L, 6 vol) and cooled to<10° C. (ice/water bath). Trifluoroacetic acid (370 mL, 551 g, 1.5 vol)was added and the solution allowed to warm to RT and stirred overnight.The solvent was removed on the rotary and azeotroped with toluene (2×500mL). The product was obtained as a thick orange oil O1-2 (359.5 g,overweight—estimated purity from NMR is 65%, giving calculated mass of234 g, 94% yield). ¹H NMR (CDCl₃, 300 MHz): δ 11.91 (s, TFA), 7.1-7.35(m, 8H), 4.6-5.65 (m, 8H), 3.79 (s, 6H), 2.6-3.2 (m, 18H), 1.1-1.9 (m,16H), 0.65-1.07 (m, 28H).

Step 4:

A solution of O1-2 (359.5 g, 65% purity, 0.190 mol) in DCM (2.5 L) wasadded slowly over 1.5 hours to a solution of propylphosphonic anhydride(50% solution in EtOAc, 670 mL, 1.126 mol) and diisopropylethylamine(392 mL, 2.25 mol) in DCM (2.5 L), maintaining the temperature between20 and 22° C. When the addition was complete, the solution was allowedto stir for a further 20 minutes and the reaction was checked forcompletion by UPLC. The solvent was removed on the rotary and replacedwith EtOAc (5 L). The solution was washed with potassium hydrogensulphate solution (1 M, 2×1 L), 3% sodium carbonate solution (2×1.5 L)and brine (1 L). The organic layer was dried over MgSO₄ and filteredthrough Fisherbrand QL100 paper twice. The solvent was removed to leavea yellow foam (233 g). This was recrystallised from ethanol (660 mL) andwater (130 mL) and the product was washed with ethanol/water (600 mL,3:1). The product was dried on the filter bed and further dried on therotary at 60° C. The product, C1, was obtained as a white solid (159.2g, 77% yield). ¹H NMR (CDCl₃, 300 MHz): δ 7.3 (m, 4H), 7.15 (m, 4H),4.4-5.67 (m, 8H), 3.76 (s, 6H), 2.7-3.1 (m, 16H), 1.16-1.8 (m, 16H),0.73-1.1 (m, 28H). UPLC (Short acid 2-95%): 1.08 min, 1095.5 Da [M+H]⁺.

Synthesis of Bis-Iodo PF1022a

Step 1:

C1 (151.5 g, 0.138 mol) was added in portions to a 33% solution of HBrin acetic acid (750 mL) and stirred at 35° C. for 6.5 hours. Thereaction mixture was cooled to 15° C. (ice/water bath) and ice/water(1.75 L) was added. A solution of 10% sodium carbonate was addedcarefully (about 2.5 L) to basify the mixture to pH 4-5. The mixture wasextracted with ethyl acetate (2 L). The organic layer was separated andwashed with saturated aqueous NaHCO₃ (2×1.5 L), and brine (1 L). Theorganic layer was dried over Na₂SO₄ and evaporated to a crisp foam (143g). The foam was recrystallised from 2-propanol (600 mL) and dried toleave the product, 01-1, as a free flowing white powder (117.0 g, 87%yield). ¹H NMR (CDCl₃, 300 MHz): δ 6.99 (m, 4H), 6.58 (m, 4H), 4.4-5.6(m, 8H), 3.62 (br s, 4H), 2.7-3.1 (m, 16H), 1.16-1.9 (m, 14H), 0.73-1.1(m, 28H). UPLC (Long acid 2-95%): 2.79 min, 980.3 Da [M+H]⁺.

Step 2:

To a solution of 01-1 (10 g, 10.2 mmol) in CH₃CN (125 mL) and added pTSA(7.1 g, 40.8 mmol, 4.0 eq) at room temperature and then cooled to −2° C.using ice-salt bath. A 1.5M solution of NaNO₂ (1.70 g, 24.5 mmol, 2.4eq) in water (15 mL) was slowly added over a period of 7 minutes whilemaintaining temperature around −1° C. After 15 minutes, CuI (8.7 g, 46.0mmol, 4.5 eq) was added over 5 minutes and rinsed with water (20 ml).Resulting brown mixture was stirred at about −1° C. for 30 minutes, andthen stirred at about −2 to 5° C. for 30 minutes without cooling.Reaction was cooled to 2° C. by adding ice into reaction and quenchedwith 25% sodium thiosulphate solution (100 mL). Organic layer wasseparated and aqueous layer extracted with ethyl acetate (2×75 ml).Combined organic solution was washed with water (100 mL) and saturatedNaHCO₃ (75 mL), brine (100 mL), dried over Mg₂SO₄ and concentrated undervacuum to get solid 16 g. Obtained solid dissolved in DCM (30 mL),adsorbed on silica gel (60 g) and filter through silica gel bed (100 g)using 50% EtOAC/hexane. Organic solution was concentrated under vacuumto a solid and dried under vacuum at 40° C. for overnight to getBis-Iodo PF1022a, (7.5 g, 62%). 1H NMR (600 MHz, CDCl₃) δ: 0.68-0.98 (m,29H), 1.24-1.7 (m, 13H), 2.67-3.07 (m, 16H), 4.36-4.43 (m, 1H),4.96-5.63 (m, 7H), 6.98-7.05 (m, 4H), 7.60-7.69 (m, 4H). LC-MS (m/z):[M+]=1200

As shown in Scheme 1c, conversion of Bis-Iodo PF1022a to Bis-CH₂ClPF1022a is accomplished by a three step sequence. Palladium catalyzedcarbonylation in an atmosphere of carbon monoxide to install thealdehyde that is then reduced with a hydride reagent to form Bis-CH₂OHPF1022a can readily be converted using standard chlorinating agent tothe Bis-CH₂Cl PF1022a intermediate. In the preparation of Bis-AldehydePF1022a a small but appreciable amount (2%-20%) of4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzaldehyde(Mono-Aldehyde PF1022a) is also formed. Mono-aldehyde PF1022a may beseparated from Bis-Aldehyde PF1022a using standard reverse phase HPLCmethods. Bis-CH₂Cl PF1022a was used as a starting material, with anappropriate Het, to prepare some of the examples of Formula 1 presentedin Tables 1-2, 6, 9, and 10 using conditions described in step 2 ofScheme 2.

Synthetic Procedures for the Preparation of Bis-CH₂Cl PF1022a (Scheme1c)

Step 1:

A 2 L pressure reactor was charged with Bis-Iodo PF1022a (130.0 g, 101.7mmol), HSi(octyl)₃ (225 g, 610.1 mmol), DMF (700 mL), TEA (131 mL, 938.8mmol) and Pd(TPP)₄ (5.6 g, 4.8 mmol) and then purged with nitrogen andcarbon monoxide. Reaction was heated to 65° C. under carbon monoxide (55psi) and stirred for 2 hours. Reaction was cooled to 22° C., slowlydiluted with ice-water (2.5 L). Solid was collected, washed with water(2×250 mL) hexane (2×200 mL) and dried under vacuum at 50° C. forovernight to get crude Bis-Aldehyde PF1022a as light brown solid (130g).

Step 2:

A 3 L round bottom flask charged with crude Bis-Aldehyde PF1022a (130 g)and methanol (1100 mL) and then cooled to −35° C. usingacetonitrile/dry-ice bath. To the mixture was slowly added NaBH₄ (5.0 g,130 mmol) while maintaining temperature below −30° C. and stirredbetween −35 and −37° C. for 1 hour. Reaction was slowly quenched withsaturated NH₄C1 (100 mL), brought to 10° C. and concentrated toapproximately ¾ volume under vacuum at 40° C. Mixture was diluted withwater (150 mL), extracted with ethyl acetate (3×150 mL). Organicsolution was dried over MgSO₄, filtered and concentrated under vacuum at45° C. to a dark brown solid. Solid was heated in 1:2 mixture ofEtOAC/Hexane (200 ml) at 60° C. and stirred at room temperature for 4hours. Solid was collected, washed with 25% ethyl acetate in hexane(2×50 mL), hexane (50 mL) and dried under vacuum to get Bis-CH₂OHPF1022a (103.5 g, 91% yield for 2 steps). 1H NMR (600 MHz, CDCl₃) δ:0.75-1.17 (m, 26H), 1.23-1.96 (m, 16H), 2.70-2.92 (m, 9H), 3.01-3.23 (m,7H), 4.45-4.53 (m, 1H), 4.65-4.74 (m, 4H), 5.03-5.14 (m, 1H), 5.19-5.72(m, 6H) 7.20-7.36 (m, 8H). LC-MS (m/z): [M+H]=1009 and [(M+23]=1031

Step 3:

A 1 L 3 neck round bottom flask was charged with Bis-CH₂OH PF1022a (98g, 90.30 mmol) and DCM (300 mL) and then cooled to 10° C. with externalice-water bath. Thionyl chloride (25 ml, 343.2 mmol) was added over 7minutes, cooling bath removed and mixture stirred at room temperature.After 1 hour, reaction was concentrated under vacuum at 35° C. to asyrup, diluted with heptane (2×75 mL) and concentrated to a solid. Brownsolid was dissolved in ethyl acetate (250 ml) and washed with aqueousNa₂CO₃ (150 mL) (50 mL saturated Na₃CO₃ solution diluted with water (100mL) to pH 7.8. Organic layer was separated and aqueous layer extractedwith ethyl acetate (2×100 mL). Combined organic solution was dried overMgSO₄, and concentrated under vacuum to a brown solid. Crude product inethyl acetate (300 ml) was stirred with activated carbon (12 g) for 4hours at room temperature, filtered through celite bed and concentratedto solid. Obtained crude material in MTBE (110 mL) was heated to reflux,diluted with hexane (50 ml) and stirred at room temperature forovernight. Solid was collected, washed with 20% MTBE/hexane (50 mL),hexane (50 mL) and dried under vacuum at 50° C. to get BisCH₂Cl PF1022aas off-white solid (98 g, 98% yield). 1H NMR (600 MHz, CDCl3) δ:0.75-1.17 (m, 26H), 1.25-1.95 (m, 16H), 2.70-2.90 (m, 9H), 3.04-3.26 (m,7H), 4.44-4.57 (m, 1H), 4.54-4.62 (m, 4H), 5.05-5.13 (m, 1H), 5.24-5.74(m, 6H) 7.20-7.39 (m, 8H). LC-MS (m/z): [M+H]=1045, [M+2]=1046,[M+3]=1047 and [M+4]=1047.

As shown in Scheme 1d, in addition to commercially available enaminones,intermediates (g ang g′) can be prepared by reacting purchased methylketone or amide monomers with N,N-dimethylformamide dimethyl acetal (DMFDMA); or by using a non-nucleophilic base such as lithium tert-butoxide(t-BuOLi) with an aminomethylene electrophile equivalent such as Gold'sreagent (Tetrahedron, 2017 3643-3651). Intermediates (g and g′) canfurther be used in a cyclization reaction (Scheme 3) to obtain Formula1A1-1 and 1F1 compounds. The variable “t” is as described in Scheme 3.

The following procedure was used in accordance with Scheme 1 d toprepare intermediate (E)-1-(dimethylamino)hex-1-en-3-one for preparinge.g., Example 1 b-205

To a solution of lithium tert-butoxide (26 mL of a 1.0M solution) in THF(25 mL) was added dropwise pentan-2-one (2.0 g, 23.0 mmol). The reactionwas stirred at room temperature for 30 min and Gold's reagent (4.3 g,26.0 mmol) was added. The reaction mixture was heated to reflux for 18hours and cooled to room temperature. Next, the crude mixture wasdiluted with sat. ammonium chloride and extracted with chloroform (2×100mL). The organic phase was dried (sodium sulfate) and concentrated undervacuum to afford intermediate 21 (2.6 g, 79%) as an oil. LC-MS (m/z):[M+H]=142.

The following procedure was used in accordance with Scheme 1 d toprepare intermediate (E)-N-((dimethylamino)methylene)propionamide, forpreparing e.g., Example 9-50

To a solution of propanamide (1 g, 8.2 mmol) in toluene (30 mL) wasadded DMF DMA (1.9 mL, 14.0 mmol). The reaction was heated to 100° C.for 18 hours and cooled to room temperature. The crude reaction wasconcentrated under vacuum to afford intermediate 31 (1.6 g, 91%). LC-MS(m/z): [M+H]=129.

Preparation of Other Intermediates that can be used to prepare examplesof Formula 1a-1f in accordance with step 2 of Scheme 2.

Step 1. A solution of 1,2-dihydro-pyrazol-3-one (4.50 g, 53.57 mmol) inpyridine (13.5 mL) was heated to 95° C. and a solution of aceticanhydride (5.57 mL, 58.93 mmol) in pyridine (13.5 mL) was added over 10minutes and continued heating for additional 3 hours. The reactionmixture was concentrated in vacuo and triturated with 10% ether-pentaneto get 1-acetyl-2,3-dihydro-1H-pyrazol-3-one (5.4 g, 80%) as whitesolid.Step 2. To a stirred solution of 1-acetyl-2,3-dihydro-1H-pyrazol-3-one(1.0 g, 7.93 mmol) in acetonitrile (20 mL) were added K₂CO₃ (2.19 g,15.86 mmol), 18-crown-6 (0.06 g, 0.24 mmol) followed by the addition of2-iodopropane (1.752 g, 10.31 mmol) drop wise at room temperature.Resulting reaction mixture was heated to reflux for 5 hours. Aftercompletion, the reaction mixture was quenched with water and extractedwith 10% methanol in dichloromethane. Combined organic layer was washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. Crude compound was purified by column chromatography(5-10% ethyl acetate in hexane) to get1-[3-(propan-2-yloxy)-1H-pyrazol-1-yl]ethan-1-one (800 mg, 60%) asyellow liquid. MS (ESI): m/z 169.1 [M+1]⁺.Step 3. To a stirred solution of 1-(3-Isopropoxy-pyrazol-1-yl)-ethanone(100 mg, 0.60 mmol) in ethanol (1 mL) was added aqueous ammoniumhydroxide (1 mL) at 0° C. and resulting mixture was stirred at RT for 1hour. After completion, the reaction mixture was concentrated underreduced pressure and azeotroped with toluene and triturated with pentaneto get 3-(propan-2-yloxy)-1H-pyrazole (45 mg, 60%) as yellow liquid. MS(ESI): m/z 126.9 [M+1]+.

To a stirred degassed solution of 4-iodo-3,5-dimethyl-1H-pyrazole (500mg, 2.25 mmol) in DMF (5 mL) was added Zn(CN)₂ (141.2 mg, 1.58 mmol)followed by Pd(dppf)Cl₂ (82.4 mg, 0.11 mmol) and Zn-dust (7.4 mg, 0.11mmol) under inert atmosphere. Resulting mixture was heated at 100° C.for 4 hours. After completion, the reaction mixture was diluted withcold water and extracted with ethyl acetate. Combined organic layer waswashed with water, brine, dried over sodium sulphate, filtered, andconcentrated under reduced pressure. Crude compound was purified bycolumn chromatography (30%-50% ethyl acetate-hexane) to afford3,5-dimethyl-1H-pyrazole-4-carbonitrile (120 mg, 44%) as light brownsolid.

Step 1. To a stirred degassed solution of 4-bromo-pyrazole-1-carboxylicacid tert-butyl ester (300 mg, 1.21 mmol) in DMF (3 mL) were addedphenyl acetylene (0.24 mL, 2.18 mmol), triethyl amine (0.84 mL, 6.05mmol), CuI (40.16 mg, 0.24 mmol) followed by Pd(PPh₃)₄ (279.58 mg, 0.24mmol). Resulting reaction mixture was heated at 70° C. for 6 hours.After completion, the reaction mixture was diluted with water andextracted with ethyl acetate. Combined organic layer was dried oversodium sulfate and concentrated under reduced pressure. Crude compoundwas purified by column chromatography (10-20% ethyl acetate in hexane)to get tert-butyl 4-(2-phenylethynyl)-1H-pyrazole-1-carboxylate (230 mg,70%) as brown liquid. MS (ESI): m/z 269.3 [M+1]+.Step 2. To a stirred solution of tert-butyl4-(2-phenylethynyl)-1H-pyrazole-1-carboxylate (2.3 g, 8.58 mmol) in DCM(5 mL) at 0° C., 2M HCl in ether (10 mL) was added drop wise and stirredat RT for 16 hours. After completion, the reaction mixture wasconcentrated under reduced pressure and co-distilled with pentane (2×10mL). The crude was further triturated with 10% ethyl acetate in hexane(2 times) to afford 4-(2-phenylethynyl)-1H-pyrazole (950 mg, 54%, HClsalt) as pale brown solid. MS (ESI): m/z 169.1 [M+1]+.

The het (heterocycle or heteroaryl) compounds in Schemes 1 and 2 wereprepared by reacting commercially available PF1022A with either MOM-Clor MOM-Br in the presence of a lewis acid such as ZnCl₂ or AlCl₃ toafford a regio-mixture (including mono-hybrids) of halomethylintermediates. The regio-mixture was subsequently treated with anappropriate het in the presence of base such as NaHCO₃ or KHCO₃ andsolvent such as acetonitrile to afford a mixture of products. The crudemixture was purified using reverse-phase HPLC to afford singleregio-isomers and mono-hybrid compounds of Formula 1 (i.e., 1A1-1,1A1-2, 1B1-1, 1B1-2, 1C1-1, 1C1-2, 1D1-1, 1E1, 1F1, and 1F2).

As shown in Scheme 3, the following intermediate (d) was generated fromthe appropriate starting bis-aldehyde PF1022a using boc-hydrazine in anon-polar aprotic solvent such as DCM or DCE. The hydrazone intermediatecan subsequently be reduced to the corresponding hydrazine (e) withhydrogen gas using a palladium catalyst such as Pd/C or Pd(OH)₂/C in aprotic solvent such as MeOH or EtOH and base such as TEA ordiisopropylethylamine. The boc-intermediate (e) can be deprotected toafford the intermediate (f) with an acid source such as TFA or HCl.Examples found in Table 1b can be synthesized from intermediate (f) in acondensation reaction using the appropriately substituted enaminone (gand g′) or aminoacetamide (g) from Scheme 1d to provide compound (h).The variable “X” in Scheme 3 represents C or N. The variable “t” of theL1 and L2 heteroaryl ring represents any heteroaryl substitution asdefined herein. The major regio-isomers are 5′ and the minor isomer at3′. Examples of Formula (1A1-1, i.e., wherein X is C) and Formula (1F1,i.e., wherein X is N) can be prepared according to this scheme.

As shown in Scheme 4, the following tertiary alcohol intermediates (kand k′) were generated from the starting bis-iodo PF1022a compound usinga Grignard reagent such as iPrMgCl·LiCl followed by addition of anappropriate electrophile. The tertiary alcohol intermediates can besubsequently converted to the Formula (s) compounds which correspond toat least Formula (1A1-3; wherein Het is pyrazole) compounds via acidicconditions using TFA and toluene, or by Mitsunobu conditions with TPPand DEAD.

The following procedures were used in accordance with Scheme 1 toprepare the emodepside analog (methylene linked morpholine), whichresults in the bis-para analog (Example 9-1) and the mono-para analog(Example 10-6). The mono-para analogs are synonymously described hereinas hybrid analogs.

Step-1: To ice-cooled suspension of A1013 (2 g, 15.0 mmol) in CH₂Cl₂ (5mL) were slowly added a solution of PF1022A (1.00 g, 2.05 mmol) inCH₂Cl₂ (5 mL) and bromomethyl methyl ether (2.0 mL, 24.5 mmol), and thenmixture stirred at room temperature for 17 hours. The reaction mixturewas poured into ice-water (50 mL) and extracted with ethyl acetate (3×25mL). The organic layer was washed with saturated aqueous NaHCO₃ (2×25mL) and brine (25 mL), dried over Na₂SO₄ and concentrated to get mixtureof un-separable intermediates (a) and (b) (1.0 g). LC-MS (m/z):[M+H]=1133 for intermediate (a) and LC-MS (m/z): [M+H]=1041 forintermediate (b).Step-2: To a solution of mixture of crude bromomethyl intermediates (a)and (b) (150 mg) in CH₂Cl₂ (3 mL) was added morpholine (0.1 mL) andstirred at room temperature for 5 hours. The reaction mixture wasdiluted with EtOAc (10 mL), washed with water (5 mL), brine, dried(Na₂SO₄), and concentrated under vacuum. The crude material was purifiedusing reverse phase (Kinetex 5 uM EVO C18 100A LC column 250×30.0 mm)eluting from 10% (MeCN/water, 0.1% TFA) to 100%, (MeCN, 0.1% TFA) over20 minutes collecting 2 peaks. Fractions were lyophilized to affordExample 9-1 (28 mg) and Example 10-6 (11 mg).

The following procedures were used in accordance with Scheme 2 toprepare representative pyrazole analogs of Formula (1); wherein Het ispyrazole (e.g., 1b-23, 2-1, and 3-1). The mono-para analogs aresynonymously described herein as hybrid analogs.

Step 1. PF1022A (2000 mg, 2.10 mmol) was dissolved in MOM-Cl (60 mL, 30vol) while stirring and zinc chloride (2.3 g, 16.9 mmol) was next added.The stirring was continued at room temperature for 48 hours. The crudereaction was concentrated under vacuum, dissolved in EtOAc (150 mL) andwashed with water and brine. The organic phase was subsequently dried(Na₂SO₄) and concentrated under vacuum to afford intermediate (c) as amixture of regio-isomers (2.34 g, 106%). LC-MS (m/z): [M+]=1046.Step 2: To a solution of chloromethyl intermediate (c) (120 mg, 0.11mmol) in MeCN (5 mL) was added 1H-pyrazole (47 mg, 0.69 mmol), NaHCO₃(60 mg, 0.69 mmol) and KI (75 mg, 0.46 mmol). The reaction mixture wasstirred at 50° C. under N₂ for 18 hours. Next, the reaction mixture wasdiluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentratedunder vacuum. The crude material was purified using reverse phase(Kinetex 5 uM EVO C18 100A LC column 250×30.0 mm) eluting from 50, 50,0.1% (MeCN, water, TFA) to 100, 0.1% (MeCN, TFA) over 20 minutescollecting 3 major peaks. Fractions were lyophilized to afford Example1b-23 (18 mg, 14%), Example (2-1) and Example 3-1 (13 mg, 10%).

Additionally, other compounds were similarly prepared using MOM-C1, forexample; Examples 9-4, 9-5, 9-6, 9-7, 9-8, 9-9, 9-10, 10-3, 10-5, 10-6,10-7, and 10-8.

Representative Examples were also prepared according to Scheme 2; forexample: Examples 9-13 and 10-4 were synthesized following the sameprocedure as for Example 1b-23, but using 1H-1,2,4-triazole in place of1H-pyrazole in Step 2. Examples 1b-24, 2-2, and 3-2 were synthesizedfollowing the same procedure as for Example 1b-24, but using4-methyl-1H-pyrazole in place of 1H-pyrazole. Examples 1b-25 and 3-3were synthesized following the same procedure as for Example 1 b-23, butusing 4-bromo-1H-pyrazole in place of 1H-pyrazole. Examples 6-1, 7-1,and 8-1 were synthesized following the same procedure as for Example1b-23, but using 2-methyl-1H-imidazole in place of 1H-pyrazole. Examples1b-26, 2-3, and 3-4 were synthesized following the same procedure as forExample 1b-23, but using 4-phenyl-1H-pyrazole in place of 1H-pyrazole.Examples 1b-27, 2-5, and 3-6 were synthesized following the sameprocedure as for Example 1b-23, but using using4-fluorophenyl-1H-pyrazole in place of 1H-pyrazole; and4-chlorophenyl-1H-pyrazole in place of 1H-pyrazole for compounds 1b-28,2-6, and 3-7. Examples 1 b-29 and 2-7 were synthesized following thesame procedure as for Example 1b-23, but using 3,5-dimethyl-1H-pyrazolein place of 1H-pyrazole. Examples 6-2 and 8-2 were synthesized followingthe same procedure as for Example 1b-23, but using 1H-imidazole in placeof 1H-pyrazole. Examples 1b-30, 2-8, and 3-9 were synthesized followingthe same procedure as for Example 1b-23, but using using4-tert-butyl-1H-pyrazole in place of 1H-pyrazole; and Examples 1b-31,2-9, and 3-10 using 4-ethyl-1H-pyrazole in place of 1H-pyrazole.Examples 6-3, 7-3, and 8-3 were synthesized following the same procedureas for Example 1b-23, but using using 2-bromo-1H-imidazole in place of1H-pyrazole; Examples 6-4, 7-4, and 8-4 using 2-ethyl-1H-imidazole inplace of 1H-pyrazole; and Examples 6-6 and 8-6 using2-tert-butyl-1H-imidazole in place of 1H-pyrazole. Examples 6-7, 7-7,and 8-7 were synthesized following the same procedure as for Example1-37, but using 2-cyclopropyl-1H-imidazole in place of 1H-pyrazole.

Examples 1a-13, 1b-93, and 2-65 were prepared from intermediateBis-CH₂Cl PF1022a (schemes 1a-c) according to the conditions in step 2of Scheme 2.

was prepared: to a solution of Bis-CH₂Cl PF1022a (120 mg, 0.11 mmol) inacetonitrile (5.7 mL, 0.02M) was added 3,5-dicyclopropyl-1H-pyrazole(25.5 mg, 0.17 mmol, 1.5 equivalents), potassium bicarbonate (45.9 mg,0.45 mmol) and potassium iodide (114 mg, 0.69 mmol). The mixture washeated to 50° C. for 18 hours. 1H-pyrazole-3,5-dicarbonitrile (34 mg,0.28 mmol) was added and the mixture heated to 50° C. for 18 hours.After allowing cooling to room temperature, the solvent was removedunder reduced pressure and the residue partitioned between water andDCM. The organics were separated, dried over MgSO₄ and evaporated. Thecrude material was purified by reverse phase HPLC to give the titleproduct as a white solid (30 mg, 21%).

was prepared: to a solution of Bis-CH₂Cl PF1022a in acetonitrile (4.8mL, 0.02M) was 4-bromo-1H-pyrazole-3-carbonitrile added (66 mg, 0.38mmol), potassium bicarbonate (38 mg, 0.38 mmol) and potassium iodide (95mg, 0.57 mmol). The mixture was heated to 50° C. for 48 hours. Aftercooling to room temperature, the solvent was removed under reducedpressure and the residue partitioned between water and DCM. The organicswere separated, dried over MgSO₄ and evaporated. The crude material waspurified by reverse phase HPLC to give the title product as a whitesolid (46 mg).

was prepared: to a solution of mono-CH₂Cl PF1022a (120 mg, 0.12 mmol) inacetonitrile (6 mL, 0.02M) was added(5-cyclopropyl-1H-pyrazol-3-yl)methanol (33 mg, 0.24 mmol), potassiumbicarbonate (24 mg, 0.24 mmol) and potassium iodide (59 mg, 0.36 mmol).The mixture was heated to 50° C. for 48 hours. After cooling to roomtemperature, the solvent was removed under reduced pressure and theresidue partitioned between water and DCM. The organics were separated,dried over MgSO₄ and evaporated. The crude material was purified byreverse phase HPLC to give the title product as a white solid (49 mg,37%).

The following procedures were used in accordance with Scheme 2 toprepare Example 9-47.

Step 1: To a stirred solution of Bis-CH₂Cl PF1022a (150 mg, 0.14 mmol)in acetonitrile (6 mL) were added2,6-Dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester(180.39 mg, 0.86 mmol), NaHCO₃ (72.41 mg, 0.86 mmol) and KI (95.40 mg,0.58 mmol) at room temperature. Resulting reaction mixture was heated at50° C. for 18 hours. After completion, the reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. Combined organic layer was dried over sodium sulfateand concentrated under reduced pressure. Crude mass was purified by prepHPLC to get tert-butyl2-[(4-{[(2R,5S,8R,11S,14R,17S,20R,23S)-14-{[4-({5-[(tert-butoxy)carbonyl]-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-2-yl}methyl)phenyl]methyl}-4,8,10,16,20,22-hexamethyl-5,11,17,23-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl]methyl}phenyl)methyl]-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carboxylate(75 mg, 37%) as white solid. MS (ESI): m/z 1389.9 [M−1]⁻.Step 2. To a stirred solution of tert-butyl2-[(4-{[(2R,5S,8R,11S,14R,17S,20R,23S)-14-{[4-({5-[(tert-butoxy)carbonyl]-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-2-yl}methyl)phenyl]methyl}-4,8,10,16,20,22-hexamethyl-5,11,17,23-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl]methyl}phenyl)methyl]-2H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carboxylate(75 mg, 0.05 mmol) in DCM (1.5 mL) was added 2 M HCl in ether (0.5 mL)at 0° C. Resulting reaction mixture was stirred at room temperature for16 hours. After completion, the reaction mixture was concentrated, andtriturated with ether to afford(3S,6R,9S,12R,15S,18R,21S,24R)-4,6,10,16,18,22-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-12,24-bis[(4-{2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-2-ylmethyl}phenyl)methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone(70 mg, HCl salt, quant) as off white solid. MS (ESI): m/z 1189.7[M−1]⁻.Step 3. To a stirred solution of(3S,6R,9S,12R,15S,18R,21S,24R)-4,6,10,16,18,22-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-12,24-bis[(4-{2H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-2-ylmethyl}phenyl)methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaoneas HCl salt (60 mg, 0.05 mmol) in formic acid (4 mL), formaldehyde (30%in water, 2 mL) was added drop wise at 60° C. After addition, thereaction mixture was heated at 100° C. for 2 hours. After completion,the reaction mixture was concentrated under reduced pressure. Crudecompound was purified by Prep-HPLC to get example 9-47 (7 mg, 11%) aswhite solid. MS (ESI): m/z 1217.2 [M−1]⁻.

As a representative example, the following procedures were used inaccordance with Scheme 3 to prepare Example 1b-108.

Step 1: To a solution of bis-aldehyde PF1022a (5.0 g, 4.9 mmol) in DCM(125 mL) was added acetic acid (300 uL, 5.5 mmol) and tert-butylN-aminocarbamate (1.9 g, 14.9 mmol). The reaction mixture was stirred atroom temperature for 24 hours to afford the bis-imine intermediate (d).LC-MS (m/z): [M+H]=1234.Step 2: To a solution of intermediate (d) (6.5 g, 5.3 mmol) in MeOH (100mL) was added Pd(OH)₂ (250 mg, 20% on carbon) andN,N-diisopropylethylamine (3.0 mL, 17.0 mmol). The mixture washydrogenated with H₂ gas at 18 p.s.i. in a Parr shaker for 1.5 h. Thereaction mixture was filtered through celite and concentrated undervacuum until ˜10 mL solvent remained. The crude solution was dilutedwith DCM (150 mL) and washed with water, brine, dried (Na₂SO₄), andsubsequently concentrated under vacuum to afford intermediate as (e) asolid. LC-MS (m/z): [M+H]=1237.Step 3: Intermediate (e) (2.0 g, 1.6 mmol) was dissolved in MeOH (75 mL)and HCl gas was bubbled in for 1 minute. The reaction mixture was heatedto 40° C. for 24 h. The reaction mixture was next concentrated undervacuum to afford intermediate (f) as a bis HCl salt. LC-MS (m/z):[M+H]=1037.Step 4: To a solution of intermediate (f) (450 mg, 0.40 mmol) inMeOH:water:AcOH (10:1:0.1, 15 mL) was added commercially available1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (225 mg, 1.62 mmol) andNaOAc (270 mg, 3.2 mmol). The reaction mixture was heated to 90° C.under microwave irradiation for 15 minutes. The crude material waspurified using reverse phase (Kinetex 5 uM EVO C18 100A LC column250×30.0 mm) eluting from 30% (MeCN/water, 0.1% TFA) to 100%, (MeCN,0.1% TFA) over 20 minutes to afford example 1b-108 (108 mg, 22%). LC-MS(m/z): [M+H]=1189.

The following procedures were used in accordance with Scheme 3 toprepare Example 1b-211.

Step 1: To a stirred solution of bis-hydrazine (Scheme 3, intermediate(f); 1200 mg, 1.08 mmol) in MeOH:water (10:1, 25 mL) was added4-(dimethylamino)-1,1-dimethoxy-but-3-en-2-one (750 mg, 4.3 mmol) andNaOAc (360 mg, 4.3 mmol). The reaction mixture was stirred at roomtemperature for 24 hours. Next, the reaction mixture was diluted withCH₂Cl₂ (150 mL) and washed with water. The organic phase was dried(Na₂SO₄) and concentrated under vacuum. The resulting crude bis-acetal(1200 mg, 0.95 mmol) was dissolved in CH₂Cl₂ (20 mL) and treated withTFA (3 mL) dropwise. The reaction was stirred at room temperature for 24hours and concentrated under reduced pressure. The crude material waspurified using reverse phase chromatography eluting from 30:70:0.1%MeCN:water:TFA to 100% MeCN:0.1% TFA over a 20 minute gradient.Fractions were lyophilized to afford2-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-[[4-[(5-formylpyrazol-1-yl)methyl]phenyl]methyl]-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrazole-3-carbaldehyde(276 mg, 25%) as a solid. MS: m/z 1165 [M+H].Step 2: To a stirred solution of the product of Step 1 (75 mg, 0.06mmol) in CH₂Cl₂ (5 mL) at −78° C. was added DAST (25 μL, 0.18 mmol). Thereaction was warmed to room temperature and stirred for 24 hours. Thereaction was subsequently cooled to −78° C. and treated with additionalDAST (25 μL, 0.18 mmol). After stirring 48 hours at room temperature,the reaction was quenched with saturated NaHCO₃ (25 mL) and diluted withCH₂Cl₂ (25 mL). The organic phase was dried (Na₂SO₄) and concentratedunder reduced pressure. The crude material was purified using reversephase chromatography eluting from 30:70:0.1% MeCN:water:TFA to 100%MeCN:0.1% TFA over a 20 min gradient. Fractions were lyophilized toafford example 1b-211 (11 mg, 14%) as a solid. MS: m/z 1209 [M+H].

As representative examples, the following procedures were used inaccordance with Scheme 4 to prepare for example: Example 1c-11 and1c-13.

Step 1. A solution of bis-iodide PF1022a (300 mg, 0.25 mmol) in dry THF(15 mL) was cooled to −78° C. and iPrMgCl·LiCl solution (1.3M in THF,1.92 mL, 2.5 mmol) was added drop wise over a period of two minutesunder argon atmosphere. Resulting mixture was warmed to −5° C. andstirred at that temperature for 20 minutes followed by addition of coldneat acetone (0.5 mL, excess) and continued stirring for additional 1 hat −5° C. Reaction mixture was quenched with saturated aqueous NH₄Clsolution (2 mL) and extracted with ethyl acetate (2×30 mL). Combinedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. Crude masswas triturated with pentane and dried to afford compound the alcohol[310 mg, mixture of bis and mono alcohol] as white solid. It was used inthe next step without further purification.Step 2. To a stirred solution of the above mixture of alcohols (k, k′;100 mg, 0.09 mmol) in toluene (5 mL) were added 4-bromo pyrazole (41.44mg, 0.28 mmol) and TFA (0.03 mL, 0.38 mmol) at room temperature.Resulting reaction mixture was heated to reflux for 16 hours. Aftercompletion, the reaction mixture was diluted with water and extractedwith 10% methanol in ethyl acetate. Combined organic layer was driedover sodium sulphate, filtered and concentrated under reduced pressure.Crude mass (180 mg) was purified by prep HPLC to afford the compound(1c-11) (18 mg, 14%) as white solid.

To a stirred solution of intermediate (k, k′) (40 mg, 0.04 mmol; Scheme4) in THF (6 mL) 3,5-bis-CF₃-pyrazole (47 mg, 0.232 mmol), TPP (60 mg,0.23 mmol) were added at room temperature under argon atmosphere.Resulting mixture was cooled to 0° C. and diethyl azodicarboxylate(DEAD; 36 μL, 0.23 mmol) was added. The mixture was warmed to roomtemperature and stirred for 48 hours. The volatiles were evaporatedunder reduced pressure and crude residue was dissolved in ethyl acetate(30 mL). Organic layer was washed with water, brine, dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure. Crude mass was purified by prep-HPLC to afford the compound(1c-13) (6 mg, 11%) as a white solid. 2 mg mono substituted product wasalso isolated after preparatory HPLC.

Mass data (ESI-MS m/z [M+H]⁺) for the respective compounds is presentedafter each of the compound names in parentheses following the respectivecompound Tables. For example: Table 1a. (1a-1).1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-bromo-3-cyano-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile(1264).

The following Formula (1A1-1) compounds (para/para) described in Tables1a and 1b were prepared in accordance with the schemes and examplesdescribed herein.

TABLE 1a Formula (1A1-1) Compounds; Assymetric Pyrazole Substitutions #3 4 5 3′ 4′ 5′ 1a-1  —CN H —CN —CN Br H 1a-2  —CN H —CN —CH₂OH H —CH₂OH1a-3  —CN H —CN

H —CH₂OH 1a-4 

H

H —CH₂OH 1a-5 

H

phenyl H —CH₂OH 1a-6 

H

H —CH₂OH 1a-7  —CN H —CN —CHF₂ H

1a-8 

H

methyl —CH₂OH H 1a-9  —CN Br H H Br —CN 1a-10 —CN H —CN —CH₂OH H

1a-11 H

H —CN H —CN 1a-12 H H phenyl —CN H —CN 1a-13

H

—CN H —CN 1a-14

H

—CH₂OH H

1a-15 H phenyl H H H H 1a-16 H H H H H 1a-17 H H H H t-butyl H 1a-18 H4-Cl-phenyl H H H H 1a-19 H phenyl H H methyl H 1a-20 H I H H methyl H1a-21 H I H H H H 1a-22 H 4-F-phenyl H H methyl H 1a-23 methyl methyl Hmethyl H 1a-24 H Br H H methyl H 1a-25 methyl

methyl H methyl H 1a-26 —CF₃ H H H H —CF₃ 1a-27 H 4-Cl-phenyl H H methylH 1a-28 phenyl H H H methyl H 1a-29 —CF₃ H H H methyl H 1a-30 H —CF₃ H Hmethyl H 1a-31 Br H H H H H 1a-32 —CN Br H H —NH₂ H 1a-33 H —NHC(O)CF₃ HH —NH₂ H 1a-34

H H H H

1a-35 isopropoxy H H H H isopropoxy 1a-36 ethoxy H H H H ethoxy 1a-37—CH₂OCH₃ H H H H —CH₂OCH₃ 1a-38 H ethoxy methyl methyl ethoxy H 1a-39 Hisopropoxy methyl methyl isopropoxy H 1a-40 H H

H H 1a-41 H H

H H 1a-42 H H

H H 1a-43 H H

H H 1a-44 H H

H H 1a-45 H H

H H 1a-46 H H Cl Cl H H

The following (1A1-1) compound names and example #'s refer to thosecompounds depicted in Table 1a. In one aspect of the invention, areFormula (1A1-1) compounds selected from the group consisting of:

-   (1a-1).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-bromo-3-cyano-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1264);-   (1a-2).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((3,5-bis(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1220);-   (1a-3).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((3-(furan-2-yl)-5-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1257);-   (1a-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-(hydroxymethyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1304);-   (1a-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-(hydroxymethyl)-3-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1297);-   (1a-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3-(furan-2-yl)-5-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1287);-   (1a-7).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1251);-   (1a-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-(hydroxymethyl)-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1235);-   (1a-9).    4-bromo-1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-bromo-5-cyano-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3-carbonitrile    (1318);-   (1a-10).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((5-cyclopropyl-3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1231);-   (1a-11). tert-butyl    (1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((3,5-dicyano-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazol-4-yl)carbamate    (1276);-   (1a-12).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-14-(4-((5-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1236);-   (1a-13).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1241);-   (1a-14).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((5-cyclopropyl-3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1261);-   (1a-15).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1185);-   (1a-16).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-bromo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1188);-   (1a-17).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-(tert-butyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (1a-18).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-(4-chlorophenyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1220);-   (1a-19).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1199);-   (1a-20).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1249);-   (1a-21).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1235);-   (1a-22).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-(4-fluorophenyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1217);-   (1a-23).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3,5-dimethyl-4-(pyrrolidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1285);-   (1a-24).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-bromo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1202);-   (1a-25).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3,5-dimethyl-4-(piperidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1299);-   (1a-26).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1245);-   (1a-27).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-(4-chlorophenyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1234);-   (1a-28).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((3-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1199);-   (1a-29).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1191);-   (1a-30).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1191);-   (1a-31).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-bromo-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-bromo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1267);-   (1a-32).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-amino-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-4-bromo-1H-pyrazole-3-carbonitrile    (1228);-   (1a-33).    N-(1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-amino-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroacetamide    (1235);-   (1a-34).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-cyclopentyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-cyclopentyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1246);-   (1a-35).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(4-((3-isopropoxy-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-isopropoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1226);-   (1a-36).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1a-37).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(4-((3-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1a-38).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[4-[(4-ethoxy-3-methyl-pyrazol-1-yl)methyl]phenyl]methyl]-18-[[4-[4-ethoxy-5-methyl-pyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1223);-   (1a-39).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-[[4-[(4-isopropoxy-3-methyl-pyrazol-1-yl)methyl]phenyl]methyl]-18-[[4-[(4-isopropoxy-5-methyl-pyrazol-1-yl)methyl]phenyl]methyl]-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1252);-   (1a-40).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((3-(tetrahydrofuran-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((5-(tetrahydrofuran-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1248);-   (1a-41).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-(3,3-difluorocyclobutyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-(3,3-difluorocyclobutyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1288);-   (1a-42).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(4-((3-(1-methoxycyclobutyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-(1-methoxycyclobutyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1276);-   (1a-43).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((3-(thietan-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((5-(thietan-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1252);-   (1a-44).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(4-((3-(isopropoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-(isopropoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1252);-   (1a-45).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((3-(phenoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((5-(phenoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1322); and-   (1a-46).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-chloro-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-chloro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1178).

TABLE 1a′ Formula (1A1-1) Table 1a Compound NMRs (1H NMR (400 Mhz,DMSO-d₆) δ ppm) Example NMR 1a-1  0.62-0.92 (m, 28 H), 1.11-1.69 (m, 14H), 2.60-3.00 (m, 16 H), 4.34 (br d, 1 H), 4.74-5.82 (m, 11 H),7.14-7.32 (m, 8 H), 7.92 (s, 1 H), 8.38 (s, 1 H) 1a-2  0.61-0.88 (m, 28H), 1.13-1.63 (m, 15 H), 2.61-3.04 (m, 15 H), 4.26-4.40 (m, 5 H), 4.96(m, 13 H), 6.07 (s, 1H), 7.01 (m, 2 H), 7.18 (br t, 4H), 7.30 (m, 2H),7.92 (s, 1H) 1a-5  0.67-0.94 (m, 28 H), 1.24-1.72 (m, 14 H), 2.63-3.13(m, 16 H), 4.32-4.53 (m, 3 H), 4.90-5.74 (m, 12 H), 6.55 (s, 1 H), 6.57(br s, 1 H), 6.63 (d, 1 H), 7.00 (d, 2 H), 7.24 (br d, 4 H), 7.37 (br d,2 H), 7.76 (s, 1 H), 7.99 (s, 1 H) 1a-6  0.44-0.67 (m, 4 H), 0.67-0.95(m, 30 H), 1.23-1.78 (m, 18 H), 2.68-3.02 (m, 15 H), 4.24-4.51 (m, 4 H),5.02-5.72 (m, 14 H), 6.55-6.64 (m, 2 H), 7.01-7.05 (m, 4 H), 7.19-7.33(m, 4 H), 7.76 (s, 1 H) 1a-8  0.43-0.65 (m, 4 H), 0.68-0.96 (m, 30 H),1.18-1.33 (m, 6 H), 1.34-1.62 (m, 6 H), 1.66-1.79 (m, 3 H), 1.99 (s, 3H), 2.68 (s, 2 H), 2.76 (br d, 4 H), 2.82-2.95 (m, 6 H), 3.03 (br s, 3H), 3.84 (br s, 1 H), 4.16 (br s, 4 H), 4.34 (s, 3 H), 4.37-4.56 (m, 2H), 4.63 (br s, 1 H), 5.00-5.72 (m, 9 H), 7.05 (br d, 2 H), 7.15 (br d,2 H), 7.27 (br d, 4 H), 7.40-7.45 (m, 1 H) 1a-10 0.43-0.64 (m, 4 H),0.67-0.94 (m, 30 H), 1.16-1.40 (m, 8 H), 1.40-1.61 (m, 4 H), 1.64-1.78(m, 3 H), 2.64-2.79 (m, 6 H), 2.81-2.94 (m, 6 H), 2.97-3.11 (m, 3 H),4.30-4.61 (m, 5 H), 4.91-5.84 (m, 10 H), 7.00-7.17 (m, 2 H), 7.19-7.27(m, 4 H), 7.35 (br d, 2 H), 7.97 (s, 1 H) 1a-13 0.46-0.63 (m, 4 H),0.68-0.95 (m, 30 H), 1.20-1.42 (m, 8 H), 1.42-1.63 (m, 4 H), 1.65-1.78(m, 3 H), 2.65-2.79 (m, 6 H), 2.82-2.96 (m, 6 H), 2.99-3.12 (m, 3 H),4.41 (br d, 1 H), 5.02-5.16-5.27 (m, 7 H), 5.34 (q, 2 H), 5.40-5.61 (m,3 H), 5.62- 5.73 (m, 4 H), 7.02-7.10 (m, 2 H), 7.21-7.29 (m, 4 H), 7.36(br d, 2 H), 7.98 (s, 1 H) 1a-14 0.45-0.65 (m, 6 H), 0.68-0.95 (m, 32H), 1.18-1.32 (m, 6 H), 1.33-1.49 (m, 3 H), 1.49-1.63 (m, 3 H),1.65-1.82 (m, 4 H), 2.67 (s, 2 H), 2.76 (br d, 4 H), 2.81-2.94 (m, 6 H),3.02 (br s, 2 H), 3.32 (s, 6 H), 4.30-4.36 (m, 2 H), 4.36-4.47 (m, 1 H),5.00- 5.25 (m, 8 H), 5.26-5.52 (m, 2 H), 5.56-5.71 (m, 2 H), 5.83-5.89(m, 1 H), 7.04 (br d, 4 H), 7.25 (br s, 4 H) 1a-15 0.65-0.95 (m, 26H),1.18-1.77 (m, 16H), 2.67-3.06 (m, 16 H), 4.39-5.70 (m, 12 H), 6.24-6.26(m, 1 H), 7.13-7.35 (m, 11 H), 7.45 (s, 1 H), 7.54 (d, 2H), 7.77-7.79(m, 1 H), 7.90-7.92 (m, 1 H), 8.23 (d, 1 H) 1a-16 0.67-0.96 (m, 26H),1.18-1.76 (m, 16H), 2.67-3.06 (m, 16 H), 4.38-5.70 (m, 12 H), 6.25-6.27(m, 1 H), 7.13-7.29 (m, 8 H), 7.44 (s, 1 H), 7.54-7.56 (m, 1 H),7.75-7.77 (m, 1 H), 8.03-8.05 (m, 1 H) 1a-17 0.66-0.95 (m, 26H), 1.18(s, 9 H) 1.19-1.75 (m, 16H), 2.67-3.06 (m, 16 H), 4.39-5.70 (m, 12 H),6.25-6.26 (m, 1 H), 7.14-7.28 (m, 8 H), 7.34 (s, 1 H), 7.44 (s, 1 H),7.54- 7.56 (m, 1 H), 7.75-7.77 (m, 1 H) 1a-18 0.67-0.95 (m, 26H),1.18-1.76 (m, 16H), 2.66-3.06 (m, 16 H), 4.39-5.71 (m, 12 H), 6.24-6.26(m, 1 H), 7.14 (d, 2 H), 7.22-7.32 (m, 6 H), 7.39 (d, 2 H), 7.42-7.44(m, 1 H), 7.57-7.60 (m, 2 H), 7.77-7.79 (m, 1 H), 7.92-7.94 (m, 1 H),8.28-8.30 (m, 1 H) 1a-19 0.65-0.94 (m, 26H), 1.15-1.74 (m, 16H), 1.98(s, 3 H), 2.66-3.08 (m, 16 H), 4.38-5.71 (m, 12H), 7.12-7.37 (m, 12H),7.48-7.50 (m, 1H), 7.54 (d, 2H), 7.89 (s, 1H), 8.22 (d, 1 H) 1a-200.66-0.94 (m, 26H), 1.18-1.73 (m, 16H), 1.98 (s, 3 H), 2.67-3.07 (m, 16H), 4.39-5.71 (m, 12 H), 7.12-7.29 (m, 9 H), 7.48-7.52 (m, 2 H),7.95-7.97 (m, 1 H) 1a-21 0.66-0.94 (m, 26H), 1.17-1.74 (m, 16 H),2.67-3.07 (m, 16 H), 4.39-5.72 (m, 12 H), 6.25 (s, 1H), 7.13-7.29 (m,8H), 7.44 (s, 1H), 7.52 (s, 1H), 7.76 (s, 1H), 7.95-7.97 (m, 1H) 1a-220.67-0.94 (m, 26H), 1.17-1.76 (m, 20 H), 1.98 (s, 3 H), 2.66-3.08 (m, 16H), 4.39-5.71 (m, 12 H), 7.12-7.30 (m, 12 H), 7.48 (s, 1 H), 7.56-7.60(m, 1 H), 7.87 (s, 1 H), 8.20- 8.22 (m, 1 H) 1a-23 0.67-0.94 (m, 26H),1.17-1.74 (m, 20H), 1.98 (s, 3 H), 2.29 (s, 3 H), 2.39 (s, 3 H),2.67-3.08 (m, 20 H), 4.39-5.71 (m, 12 H), 7.06 (d, 2 H), 7.13 (d, 2 H),7.23-7.31 (m, 5 H), 7.48-7.50 (m, 1 H) 1a-24 0.67-0.94 (m, 26H),1.17-1.73 (m, 16H), 1.98 (s, 3 H), 2.67-3.08 (m, 16 H), 4.39-5.71 (m, 12H), 7.12-7.30 (m, 9 H), 7.48-7.52 (m, 2 H), 8.02-8.04 (m, 1 H) 1a-250.67-0.94 (m, 26H), 1.17-1.76 (m, 22 H), 1.98 (s, 3 H), 2.27 (s, 3 H),2.36 (s, 3 H), 2.67-3.06 (m, 20 H), 4.39-5.71 (m, 12 H), 7.06 (d, 2 H),7.13 (d, 2 H), 7.23-7.30 (m, 5 H), 7.48-7.50 (m, 1 H) 1a-26 0.65-0.93(m, 26H), 1.17-1.76 (m, 16 H), 2.67-3.08 (m, 16 H), 4.39-5.73 (m, 12 H),6.72 (s, 1 H), 6.94 (s, 1 H), 7.05 (d, 2H), 7.22-7.32 (m, 6 H), 7.73 (s,1 H), 8.06 (s, 1 H) 1a-27 0.67-0.94 (m, 26H), 1.18-1.75 (m, 16 H), 1.98(s, 3 H), 2.66-3.06 (m, 16 H), 4.39-5.70 (m, 12 H), 7.12 (d, 2 H),7.21-7.30 (m, 7 H), 7.48 (br s, 1 H), 7.58 (d, 2 H), 7.91 (s, 1 H),8.26-8.28 (m, 1 H) 1a-28 0.67-0.94 (m, 26H), 1.18-1.74 (m, 16 H), 1.98(s, 3 H), 2.65-3.07 (m, 16 H), 4.39-5.70 (m, 12 H), 6.72 (s, 1 H), 7.13(d, 2 H), 7.21-7.30 (m, 7 H), 7.35-7.48 (m, 4 H), 7.77 (d, 2 H), 7.84(s, 1 H) 1a-29 0.67-0.94 (m, 26H), 1.18-1.76 (m, 16 H), 1.98 (s, 3 H),2.67-3.08 (m, 16 H), 4.39-5.73 (m, 12 H), 7.13 (d, 2 H), 7.21-7.32 (m, 7H), 7.48 (br s, 1 H), 7.88 (s, 1 H), 8.46-8.48 (m, 1 H) 1a-30 0.67-0.94(m, 26H), 1.18-1.76 (m, 16 H), 1.98 (s, 3 H), 2.67-3.08 (m, 16 H),4.39-5.73 (m, 12 H), 6.72 (s, 1 H), 7.13 (d, 2H), 7.21-7.32 (m, 7 H),7.48 (br s, 1 H), 8.06 (s, 1 H) 1a-31 0.67-0.95 (m, 27 H) 1.17-1.31 (m,7 H) 1.34 (br s, 2 H) 1.43 (br s, 2 H) 1.47-1.74 (m, 6 H) 2.64-2.80 (m,6 H) 2.80-2.95 (m, 7 H) 3.03 (br s, 3 H) 4.41 (br d, J = 7.70 Hz, 1 H)4.99-5.16 (m, 3 H) 5.18-5.37 (m, 6 H) 5.38-5.46 (m, 1 H) 5.47-5.57 (m, 1H) 5.63-5.73 (m, 1 H) 6.38 (s, 1 H) 6.49 (s, 1 H) 7.06 (br d, J = 7.58Hz, 2 H) 7.19 (br d, J = 7.70 Hz, 2 H) 7.29 (br s, 4 H) 7.58 (s, 1 H)7.84 (s, 1 H) 1a-32 0.74-0.87 (m, 28 H), 1.27-1.71 (m, 15 H), 2.68-3.04(m, 16 H), 5.04-5.76 (m, 12 H), 7.16 (m, 3 H), 7.27 (m, 6H), 7.64 (br s,1 H), 9.13 (br s, 2 H) 1a-34 0.67-0.94 (m, 26 H), 1.24-1.90 (m, 30 H),2.66-3.01 (m, 18 H), 4.35-4.45 (m, 1 H), 5.01-5.70 (m, 13 H), 6.05 (s, 1H), 6.10 (s, 1 H), 6.98-7.60 (m, 10 H) 1a-35 0.69-0.94 (m, 25 H),1.20-1.69 (m, 29 H), 2.67-3.02 (m, 16 H), 4.42-4.59 (m, 3 H), 5.02-5.68(m, 11 H), 7.05-7.25 (m, 11 H), 7.54 (bs, 1 H) 1a-36 0.61-0.99 (m, 27H), 1.15-1.77 (m, 21 H), 2.64-2.95 (m, 13 H), 2.96-3.11 (m, 3 H),3.98-4.15 (m, 4 H), 4.37-4.46 (m, 1 H), 4.97-5.74 (m, 13 H), 7.05 (br d,2 H), 7.12 (br d, 2 H), 7.20-7.32 (m, 5 H), 7.56 (m, 1 H) 1a-370.68-0.94 (m, 26H), 1.18-1.75 (m, 16 H), 2.67-3.07 (m, 16 H), 3.20-3.22(m, 6 H), 4.29 (s, 2 H), 4.38-5.71 (m, 14 H), 6.22 (s, 1 H), 6.28 (s, 1H), 7.06 (d, 2 H), 7.15 (d, 2 H), 7.25-7.28 (m, 4 H), 7.42 (s, 1 H),7.72 (s, 1 H). 1a-38 0.71-0.95 (m, 25 H), 1.23-1.34 (m, 12 H), 1.36-1.70(m, 10 H), 2.00 (s, 6 H), 2.67- 3.04 (m, 16 H), 3.38-3.91 (m, 4 H),4.40-4.43 (m, 1 H), 5.06-5.72 (m, 12 H), 6.98- 7.13 (m, 4 H), 7.25-7.41(m, 6 H) 1a-39 0.70-0.96 (m, 26 H), 1.19-1.66 (m, 26 H), 1.98 (s, 6 H),2.67-3.02 (m, 16 H), 4.01- 4.32 (m, 4 H), 4.40-4.43 (m, 1 H), 5.06-5.35(m, 11 H), 6.97-7.13 (m, 4 H), 7.18- 7.43 (m, 6 H)

TABLE 1b Formula (1A1-1) Compounds; Symmetric (bis) PyrazoleSubstitutions # 3 and 3′ 4 and 4′ 5 and 5′ 1b-1 methyl —NH₂ methyl 1b-2—CN Cl H 1b-3 H —NHC(O)OCH₃ H 1b-4 H

H 1b-5 H —NHC(O)NHC(CH₃)₃ H 1b-6 H —NH₂ H 1b-7 —CH₂CN H methyl 1b-8—CH₂OH H

1b-9

H H 1b-10 H —NHC(O)OC(CH₃)₃ H 1b-11 H

H 1b-12 H —NHC(O)OCH₂CF₃ H 1b-13 H

H 1b-14

H

1b-15 —CF₃ H —CF₃ 1b-16 methyl OH methyl 1b-17 H F H 1b-18 H —OH H 1b-19H isopropoxy H 1b-20 H —SCH₃ H 1b-21 H ethoxy H 1b-22 H

H 1b-23 H H H 1b-24 H methyl H 1b-25 H Br H 1b-26 H phenyl H 1b-27 H4-F-phenyl H 1b-28 H 4-Cl-phenyl H 1b-29 methyl H methyl 1b-30 H t-butylH 1b-31 H ethyl H 1b-32 H ethynyl H 1b-33 H pyridin-4-yl H 1b-34 H —CF₃H 1b-35 H Cl H 1b-36 methyl methyl methyl 1b-37 H isopropyl H 1b-38 H—C(O)CH₃ H 1b-39 H —C(O)OCH₂CH₃ H 1b-40 H

H 1b-41 H

H 1b-42 H

H 1b-43 methyl Br H 1b-44 methyl Br methyl 1b-45 H

H 1b-46 H I H 1b-47 H propyl H 1b-48 methyl ethyl methyl 1b-49 H

H 1b-50 H

H 1b-51 methyl Cl methyl 1b-52 H methoxy H 1b-53 H —C(O)NHCH₃ H 1b-54 H

H 1b-55 isopropyl H isopropyl 1b-56 H —C(O)N(CH₃)₂ H 1b-57 methyl propylmethyl 1b-58 methyl —NO₂ methyl 1b-59 H —S(O)₂CH₃ H 1b-60 H —SCH(CH₃)₂ H1b-61 H

H 1b-62 H —CHF₂ H 1b-63 Br H H 1b-64 I H H 1b-65 methyl —CH₂CH₂OH methyl1b-66 —CN H —CN 1b-67

H H 1b-68 phenyl H H 1b-69 —CF₃ H H 1b-70 H —NO₂ H 1b-71 H pyridin-2yl H1b-72 H —NHC(O)OCH₃ H 1b-73 H 4-methyl-pyridin-3yl H 1b-74 H

H 1b-75 H —CH₂CH₂OH H 1b-76 H —NHS(O)₂CH₃ H 1b-77 H pyridin-3yl H 1b-78H cyclopentyl H 1b-79 isopropyl H H 1b-80 methyl

methyl 1b-81 t-butyl H H 1b-82

H H 1b-83 —CH₂OH H —CH₂OH 1b-84 methyl —NHC(O)OCH₃ methyl 1b-85 methyl

methyl 1b-86 H

H 1b-87 H

H 1b-88 H —CH₂NHC(O)CH₃ H 1b-89 —CHF₂ H —CHF₂ 1b-90 H —C(O)NH₂ H 1b-91 H

H 1b-92 methyl —S(O)₂NH₂ methyl 1b-93 —CN Br H 1b-94 methyl H H 1b-95ethyl H H 1b-96 Cl H H 1b-97 —CH₂OH H H 1b-98 —CH₂NH₂ H H 1b-99—NHC(O)CH₃ H H 1b-100 —C(O)OC(CH₃)₃ H H 1b-101 H —S(O)₂NH₂ H 1b-102 H

H 1b-103 —CN H H 1b-104 ethoxy H H 1b-105

H H 1b-106

H H 1b-107 H

H 1b-108 H H

1b-109 H

H 1b-110 methyl F methyl 1b-111

H H 1b-112 H

H 1b-113 H

H 1b-114 H

H 1b-115 methoxy H H 1b-116 H

H 1b-117 methyl —CN methyl 1b-118 H

H 1b-119 H

H 1b-120 pyridin-2yl H H 1b-121 —NO₂ H H 1b-122

—NO₂

1b-123 ethyl —NO₂ ethyl 1b-124 —CH₂OH methyl —CF₃ 1b-125 —CN phenyl H1b-126 H H isopropyl 1b-127 H H t-butyl 1b-128 H H phenyl 1b-129 H H

1b-130 methyl —CF₃ methyl 1b-131

H H 1b-132 —S(O)₂NH₂ H H 1b-133 ethyl —NH₂ ethyl 1b-134

H H 1b-135 methyl —CN H 1b-136 —CN methyl H 1b-137 No Example 1b-138pyridin-4yl H H 1b-139 pyridin-3yl H H 1b-140 H —OCHF₂ H 1b-141 H

H 1b-142 H

H 1b-143 —NH₂ H H 1b-144 H H —NH₂ 1b-145

—NH₂

1b-146 H

H 1b-147 No example 1b-148

H H 1b-149 H H

1b-150 H —OCH₂CF₃ H 1b-151 isopropoxy H H 1b-152 H methyl methyl 1b-153H H

1b-154 H H

1b-155 H —CH₂OCH₃ H 1b-156 —OCHF₂ H H 1b-157 H —CH₂OCH₂CH₃ H 1b-158methyl —CH₂OH H 1b-159 ethoxy H methyl 1b-160 H H methyl 1b-161

H H 1b-162 —CF₃ —CH₂OH H 1b-163 methyl H ethoxy 1b-164 isopropoxy Hmethyl 1b-165 H H ethyl 1b-166 H H —CH₂OCH₃ 1b-167 H isopropoxy H 1b-168methoxy H methyl 1b-169 ethyl H ethoxy 1b-170

H ethoxy 1b-171 H ethoxy H 1b-172 H isobutoxy H 1b-173 H H pyridin-2yl1b-174 H

H 1b-175 H

H 1b-176 H H —CH₂OCH₂CH₃ 1b-177 H H

1b-178 phenyl H ethoxy 1b-179 H

H 1b-180 H

H 1b-181 methyl H

1b-182 H

H 1b-183 H

H 1b-184 H —CH₂OCH(CH₃)₂ H 1b-185 H —OCH₂CH₂NH₂ H 1b-186 ethyl H methyl1b-187 methyl H ethyl 1b-188 methyl isopropoxy methyl 1b-189 H H

1b-190 H H

1b-191 methyl ethoxy methyl 1b-192 H —N(CH₃)₂ H 1b-193 H —N(CH₂CH₃)₂ H1b-194 —CN H methyl 1b-195

H H 1b-196 —S(O)₂NH₂ H H 1b-197 H ethoxy methyl 1b-198 methyl ethoxy H1b-199 methyl isopropoxy H 1b-200 No example 1b-201 H —OCH₂OCH₃ H 1b-202H

H 1b-203 H —OCH₂CH₂OCH₃ H 1b-204 No example 1b-205 H H propyl 1b-206 H H

1b-207 H H

1b-208 H H

1b-209 H H isobutyl 1b-210 H H sec-butyl 1b-211 H H —CHF₂ 1b-212 H H

1b-213 H H

1b-214 H H

1b-215 H H

1b-216 H H

1b-217 H H

1b-218 H H

1b-219 H H

1b-220 H H —C(CH₃)₂OCH₃ 1b-221 H H

1b-222 H H

1b-223 H H

1b-224 H H

1b-225 H H

1b-226 H H

1b-227 H H

1b-228 H H —CH₂OCH(CH₃)₂ 1b-229 H H

1b-230 H H

1b-231 H H

1b-232 H H

1b-233 H H

1b-234 H H

1b-235 H H

The following Formula (1A1-1) compound names and example #'s refer tothose compounds depicted in Table 1b. In one aspect of the invention,are Formula (1A1-1) compounds selected from the group consisting of:

-   (1b-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1b-2).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(4-chloro-1H-pyrazole-3-carbonitrile)    (1229);-   (1b-3). dimethyl    ((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))dicarbamate    (1256);-   (1b-4).    1,1′-((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))bis(3-(4-(trifluoromethyl)-phenyl)urea)    (1215);-   (1b-5).    1,1′-((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))bis(3-(tert-butyl)urea)    (1339);-   (1b-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-amino-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1140);-   (1b-7).    2,2′-((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(5-methyl-1H-pyrazole-1,3-diyl))diacetonitrile    (1216);-   (1b-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclopropyl-3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (1b-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(thiophen-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1275);-   (1b-10). di-tert-butyl    ((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))dicarbamate    (1241);-   (1b-11).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(1H-pyrrol-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1240);-   (1b-12). bis(2,2,2-trifluoroethyl)    ((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))dicarbamate    (1392);-   (1b-13).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(thiazol-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1276);-   (1b-14).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1268);-   (1b-15).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[(4-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1381);-   (1b-16).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(4-hydroxy-3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1196);-   (1b-17).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1145);-   (1b-18).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-hydroxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1141);-   (1b-19).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis[[4-[(4-isopropoxypyrazol-1-yl)methyl]phenyl]methyl]-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1225);-   (1b-20).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-[(4-methylsulfanylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1201);-   (1b-21).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(4-ethoxypyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1199);-   (1b-22).    N′-hydroxy-1-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-[[4-[[4-[(Z)—N′-hydroxycarbamimidoyl]pyrazol-1-yl]methyl]phenyl]methyl]-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrazole-4-carboxamidine    (1227);-   (1b-23).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-(pyrazol-1-ylmethyl)phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1110);-   (1b-24).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1148);-   (1b-25).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(4-bromopyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1268).-   (1b-26).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-[(4-phenylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1262);-   (1b-27).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[[4-(4-fluorophenyl)pyrazol-1-yl]methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1298);-   (1b-28).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[[4-(4-chlorophenyl)pyrazol-1-yl]methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1332);-   (1b-29).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(3,5-dimethylpyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1166);-   (1b-30).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(4-tert-butylpyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1222);-   (1b-31).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(4-ethylpyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1166);-   (1b-32).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(4-ethynyl-1H-pyrazol-1    yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1156);-   (1b-33).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyridin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (1b-34).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1245);-   (1b-35).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-chloro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1178);-   (1b-36).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3,4,5-trimethyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (1b-37).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-isopropyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (1b-38).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-acetyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1193);-   (1b-39). diethyl    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-4-carboxylate)    (1253);-   (1b-40).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1336);-   (1b-41).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1304);-   (1b-42).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1332);-   (1b-43).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-bromo-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1295);-   (1b-44).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1323);-   (1b-45).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1189);-   (1b-46).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1361);-   (1b-47).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (1b-48).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-ethyl-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1222);-   (1b-49).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(piperidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1404);-   (1b-50).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(morpholinosulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1408);-   (1b-51).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1234);-   (1b-52).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-methoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1169);-   (1b-53).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(N-methyl-1H-pyrazole-4-carboxamide)    (1223);-   (1b-54).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyrrolidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1376);-   (1b-55).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-diisopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1278);-   (1b-56).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(N,N-dimethyl-1H-pyrazole-4-carboxamide)    (1252);-   (1b-57).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-dimethyl-4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (1b-58).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1255);-   (1b-59).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(methylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1266);-   (1b-60).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-(isopropylthio)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1258);-   (1b-61).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(azetidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1348);-   (1b-62).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1209);-   (1b-63).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-bromo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1267);-   (1b-64).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1361);-   (1b-65).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-66).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-3,5-dicarbonitrile)    (1209);-   (1b-67).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1189);-   (1b-68).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1262);-   (1b-69).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1245);-   (1b-70).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1199);-   (1b-71).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (1b-72).    N,N′-((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))diacetamide    (1223);-   (1b-73).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(6-methyl    pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1292);-   (1b-74).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(N-cyclopropyl-1H-pyrazole-4-carboxamide)    (1276);-   (1b-75).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(2-hydroxyethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1b-76).    N,N′-((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))dimethanesulfonamide    (1296);-   (1b-77).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (1b-78).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-cyclopentyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1246);-   (1b-79).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-isopropyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (1b-80).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-dimethyl-4-(pyrrolidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1432);-   (1b-81).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-(tert-butyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1222);-   (1b-82).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(thiophen-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1274);-   (1b-83).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-bis(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1229);-   (1b-84).    N,N′-((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(3,5-dimethyl-1H-pyrazole-1,4-diyl))diacetamide    (1280);-   (1b-85).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-dimethyl-4-(piperidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1460);-   (1b-86).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1266);-   (1b-87).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1266);-   (1b-88).    N,N′-(((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))bis(methylene))diacetamide    (1252);-   (1b-89).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1309);-   (1b-90).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-4-carboxamide)    (1195);-   (1b-91). di-tert-butyl    (((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))bis(methylene))dicarbamate    (1368);-   (1b-92).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((3,5-dimethyl-4-sulfamoyl-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide    (1324);-   (1b-93).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(4-bromo-1H-pyrazole-3-carbonitrile)    (1317);-   (1b-94).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1137);-   (1b-95).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-ethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (1b-96).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-chloro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1178);-   (1b-97).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1169);-   (1b-98).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1167);-   (1b-99).    N,N′-((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,3-diyl))diacetamide    (1223);-   (1b-100). di-tert-butyl    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-3-carboxylate)    (1310);-   (1b-101).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-14-(4-((4-sulfamoyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-4-sulfonamide    (1268);-   (1b-102).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(phenylethynyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1310);-   (1b-103).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-3-carbonitrile)    (1159);-   (1b-104).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1b-105).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-morpholino-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1280);-   (1b-106).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-cyclobutyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1218);-   (1b-107).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1272);-   (1b-108).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1189);-   (1b-109).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1274);-   (1b-110).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-fluoro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1201);-   (1b-111).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-(furan-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1241);-   (1b-112).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(3-methylbut-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1242);-   (1b-113).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(cyclopropylethynyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1238);-   (1b-114).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(3,3-dimethylbut-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1270);-   (1b-115).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1169);-   (1b-116).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1278);-   (1b-117).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(3,5-dimethyl-1H-pyrazole-4-carbonitrile)    (1215);-   (1b-118).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(prop-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1185);-   (1b-119).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(but-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1214);-   (1b-120).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (1b-121).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-nitro-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1199);-   (1b-122).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-dicyclopropyl-4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1360);-   (1b-123).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-diethyl-4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1312);-   (1b-124).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-(hydroxymethyl)-4-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1333);-   (1b-125).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(4-phenyl-1H-pyrazole-3-carbonitrile)    (1312);-   (1b-126).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-isopropyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194)-   (1b-127).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(tert-butyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1222);-   (1b-128).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1262);-   (1b-129).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclobutyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1218);-   (1b-130).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-dimethyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1301);-   (1b-131).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1265);-   (1b-132).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-14-(4-((3-sulfamoyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3-sulfonamide    (1267);-   (1b-133).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-amino-3,5-diethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1252);-   (1b-134).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-(4-methoxyphenyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1322);-   (1b-135).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(3-methyl-1H-pyrazole-4-carbonitrile)    (1187);-   (1b-136).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(4-methyl-1H-pyrazole-3-carbonitrile)    (1187);-   (1b-137). No Example;-   (1b-138).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(pyridin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (1b-139).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (1b-140).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(difluoromethoxy)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1241);-   (1b-141).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-cyclobutoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (1b-142).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(oxetan-3-yloxy)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-143).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-amino-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1139);-   (1b-144).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-amino-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1139);-   (1b-145).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-amino-3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1300);-   (1b-146).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(cyclopropylmethoxy)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (1b-147). No example;-   (1b-148).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-cyclopentyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1246);-   (1b-149).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(4-methoxyphenyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1322);-   (1b-150).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(2,2,2-trifluoroethoxy)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1305);-   (1b-151).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-isopropoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1226);-   (1b-152).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (1b-153).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(4-chlorophenyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1330);-   (1b-154).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclopentyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1246);-   (1b-155).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1b-156).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-(difluoromethoxy)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1241);-   (1b-157).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(ethoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1226);-   (1b-158).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(hydroxymethyl)-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1b-159).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-ethoxy-5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1226);-   (1b-160).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1137);-   (1b-161).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-cyclobutoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (1b-162).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1305);-   (1b-163).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-ethoxy-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1226);-   (1b-164).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-isopropoxy-5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-165).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-ethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (1b-166).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1b-167).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-isopropoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,24-pentamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1212);-   (1b-168).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxy-5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (1b-169).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-ethoxy-3-ethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-170).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-cyclopropyl-5-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1278);-   (1b-171).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(2-(4-ethoxy-1H-pyrazol-1-yl)propan-2-yl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-172).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-isobutoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-173).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (1b-174).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(thiazol-2-yloxy)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1308);-   (1b-175).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyridin-2-yloxy)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1296);-   (1b-176).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(ethoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1226);-   (1b-177).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(6-methylpyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1292);-   (1b-178).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-ethoxy-3-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1350);-   (1b-179).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-morpholino-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1280);-   (1b-180). di-tert-butyl    ((((((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-1,4-diyl))bis(oxy))bis(ethane-2,1-diyl))dicarbamate    (1428);-   (1b-181).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclopropyl-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1218);-   (1b-182).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyrrolidin-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1248);-   (1b-183).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(piperidin-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1276);-   (1b-184).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-(isopropoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-185).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(2-aminoethoxy)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1228);-   (1b-186).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((5-ethyl-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3-ethyl-5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (1b-187).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-ethyl-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (1b-188).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-isopropoxy-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1282);-   (1b-189).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1300);-   (1b-190).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(6-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1324);-   (1b-191).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-ethoxy-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-192).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(dimethylamino)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1196);-   (1b-193).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(diethylamino)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1252);-   (1b-194).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(5-methyl-1H-pyrazole-3-carbonitrile)    (1187)-   (1b-195).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-[(3-pyrazin-2-ylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1264);-   (1b-196).    1-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-14-[[4-[(3-sulfamoylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrazole-3-sulfonamide    (1265);-   (1b-197).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(4-ethoxy-5-methyl-pyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1224);-   (1b-198).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(4-ethoxy-3-methyl-pyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1224);-   (1b-199).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis[[4-[(4-isopropoxy-3-methyl-pyrazol-1-yl)methyl]phenyl]methyl]-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1252);-   (1b-200). No example;-   (1b-201).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis[[4-[[4-(methoxymethoxy)pyrazol-1-yl]methyl]phenyl]methyl]-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1228);-   (1b-202).    3-[1-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-[[4-[[4-(2-carboxyethoxy)pyrazol-1-yl]methyl]phenyl]methyl]-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrazol-4-yl]oxypropanoic    acid (1284);-   (1b-203).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis[[4-[[4-(2-methoxyethoxy)pyrazol-1-yl]methyl]phenyl]methyl]-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1256);-   (1b-204). No example;-   (1b-205).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-propyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1193);-   (1b-206).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(cyclopropylmethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1217);-   (1b-207).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(2-methylpyrimidin-5-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1293);-   (1b-208).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1265);-   (1b-209).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-isobutyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1221);-   (1b-210).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(sec-butyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1221);-   (1b-211).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(difluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1209);-   (1b-212).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(1-methoxyethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1225);-   (1b-213).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(4-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1305);-   (1b-214).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(2-methoxy-2-methylpropyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1281);-   (1b-215).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(1-fluorocyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1225);-   (1b-216).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(2,2-difluorocyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1261);-   (1b-217).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(1-chlorocyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1258);-   (1b-218).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(1-aminocyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1220);-   (1b-219).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(1-methylcyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1218);-   (1b-220).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(2-methoxypropan-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (1b-221).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(3-methyloxetan-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (1b-222).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(2-methylcyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1218);-   (1b-223).    (3S,6R,12R,15S,18R,21S,24R)-4,6,10,16,18,22-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-12,24-bis[(4-{[5-(oxolan-2-yl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1248);-   (1b-224).    (3S,6R,9S,12R,18R,21S,24R)-6,18-bis[(4-{[5-(3,3-difluorocyclobutyl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-ocatone    (1288);-   (1b-225).    (3S,6R,9S,12R,18R,21S,24R)-6,18-bis[(4-{[5-(1-methoxycyclobutyl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-ocatone    (1276);-   (1b-226).    (3S,6R,12R,15S,18R,21S,24R)-4,6,10,16,18,22-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-12,24-bis[(4-{[5-(phenoxymethyl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1320);-   (1b-227).    (3S,6R,12R,15S,18R,21S,24R)-4,6,10,16,18,22-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-12,24-bis[(4-{[5-(thietan-3-yl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-ocatone    (1252);-   (1b-228).    (3S,6R,12R,15S,18R,21S,24R)-4,6,10,16,18,22-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-12,24-bis({[4-({5-[(propan-2-yloxy)methyl]-1H-pyrazol-1-yl}methyl)phenyl]methyl})-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1252);-   (1b-229).    (3S,6R,9S,12R,18R,21S,24R)-6,18-bis[(4-{[5-(1-methoxycyclopentyl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1304);-   (1b-230).    (3S,6R,9S,12R,18R,21S,24R)-6,18-bis[(4-{[5-(2-hydroxy-2-methylpropyl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-ocatone    (1251);-   (1b-231).    (3S,6R,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(tetrahydrofuran-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1249);-   (1b-232).    (3S,6R,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(thiazol-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1275);-   (1b-233).    (3S,6R,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(5-methylfuran-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1269);-   (1b-234).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(2,2-dimethylcyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1246); and-   (1b-235).    (1S,3S)-3-(1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((5-((1R,3R)-3-cyano-2,2-dimethylcyclopropyl)-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazol-5-yl)-2,2-dimethylcyclopropane-1-carbonitrile    (1296).

TABLE 1b′ Formula (1A1-1) Table 1b Compound NMR's (1H NMR (400M Hz,DMSO-d₆) δ ppm) Example NMR 1b-3  0.67-0.82 (m, 18 H), 0.82-0.96 (m, 9H), 1.16-1.38 (m, 8 H), 1.40-1.62 (m, 5 H), 1.65-1.74 (m, 2 H), 2.67 (s,2 H), 2.72 (s, 2 H), 2.77 (s, 2 H), 2.81-2.94 (m, 7 H), 2.98-3.09 (m, 3H), 3.32 (s, 9 H), 3.60 (s, 6 H), 4.41 (br d, 1 H), 5.00-5.17 (m, 3 H),5.21 (s, 5 H), 5.26-5.53 (m, 2 H), 5.64- 5.72 (m, 1 H), 7.15 (br d, 4H), 7.23- 7.34 (m, 6 H), 7.67 (br s, 2 H), 9.38 (s, 2 H) 1b-4  0.68-0.82(m, 18 H), 0.82-0.96 (m, 10 H), 1.22 (br d, 6 H), 1.25-1.37 (m, 3 H),1.38-1.76 (m, 8 H), 2.67 (s, 4 H), 2.70-2.96 (m, 9 H), 2.99-3.10 (m, 3H), 4.38- 4.48 (m, 1 H), 5.00-5.07 (m, 1 H), 5.10 (br d, 2 H), 5.14-5.29(m, 4 H), 5.36 (q, 1 H), 5.48-5.59 (m, 1 H), 5.64-5.74 (m, 1 H), 7.19(br d, 4 H), 7.29 (br d, 4 H), 7.42 (s, 2 H), 7.55-7.67 (m, 6 H), 7.80(d, 2 H), 8.83 (br s, 2 H), 9.31 (br s, 2 H) 1b-6  0.67-0.97 (m, 30 H),1.17-1.39 (m, 10 H), 1.42 (s, 3 H), 1.46-1.74 (m, 7 H), 2.69 (br d, 4H), 2.75-2.95 (m, 9 H), 2.98-3.11 (m, 3 H), 5.02-5.25 (m, 2 H), 5.29-5.56 (m, 2 H), 5.64-5.76 (m, 2 H), 7.16 (br d, 4 H), 7.22-7.34 (m, 6 H),7.64 (br s, 2 H), 9.13 (br s, 2 H) 1b-14  0.41-0.61 (m, 8 H), 0.70-0.94(m, 32 H), 1.24-1.75 (m, 19 H), 2.67-3.01 (m, 16 H), 4.39-4.44 (m, 1 H),5.01-5.68 (m, 14 H), 7.03-7.05 (m, 5 H), 7.23-7.25 (m, 5 H) 1b-15 0.77-0.92 (m, 26 H), 1.27-1.72 (m, 16 H), 2.66-3.05 (m, 16 H), 4.39-4.41(m, 1 H), 5.01-5.69 (m, 11 H), 7.11-7.13 (m, 4 H), 7.32-7.33 (m, 4 H),7.63 (s, 2 H) 1b-16  0.80-0.95 (m, 26 H), 1.28-1.70 (m, 16 H), 1.96-2.01(m, 12 H), 2.67-3.01 (m, 16 H), 4.39-4.42 (m, 1 H), 5.05-5.68 (m, 11 H),6.95-6.97 (m, 4 H), 7.24-7.25 (m, 4 H), 7.52 (br s, 2 H) 1b-17 0.65-0.94 (m, 24 H), 1.23-1.73 (m, 17 H), 2.67-3.03 (m, 16 H), 4.37-4.45(m, 1 H), 5.01-5.75 (m, 12 H), 7.16-7.18 (m, 4 H), 7.27-7.29 (m, 4 H),7.46 (s, 2 H), 7.91 (s, 2 H) 1b-18  0.67-0.95 (m, 24 H), 1.19-1.70 (m,17 H), 2.68-3.02 (m, 16 H), 4.40-4.42 (m, 1 H), 5.02-5.70 (m, 12 H),6.99 (s, 2 H), 7.10-7.12 (m, 4 H), 7.18-7.27 (m, 6 H), 8.39 (s, 2 H)1b-19  0.59-1.04 (m, 26 H), 1.08-1.84 (m, 28 H), 2.60-3.18 (m, 16 H),3.99-4.21 (m, 2 H), 4.38-4.47 (m, 1 H), 4.97-5.82 (m, 11 H), 6.95-7.68(m, 12 H) 1b-20  0.67-0.95 (m, 26 H), 1.17-1.76 (m, 16 H,) 2.28 (s, 6H), 2.65-2.95 (m, 13 H,) 3.00-3.11 (m, 3 H), 4.35-4.47 (m, 1 H),4.96-5.57 (m, 10 H), 5.63-5.75 (m, 1 H), 7.18 (m, 4 H), 7.25-7.33 (m, 4H), 7.45-7.52 (m, 2 H), 7.83-7.90 (m, 2 H) 1b-21  0.62-0.99 (m, 26 H),1.16-1.78 (m, 22 H), 2.64-2.95 (m, 13 H), 2.98-3.13 (m, 3 H), 3.81-3.90(m, 4 H), 4.38-4.49 (m, 1 H), 4.99-5.74 (m, 11 H), 7.08-7.31 (m, 10 H,)7.42-7.53 (m, 2 H) 1b-22  0.62-0.99 (m, 26 H), 1.13-1.84 (m, 16 H),2.61-2.97 (m, 13 H) 3.01-3.20 (m, 3 H) 4.34-4.53 (m, 1 H) 4.87-5.80 (m,11 H) 7.16-7.39 (m, 8 H), 8.06 (s, 2 H), 8.47 (s, 2 H), 8.74-9.05 (m, 2H), 10.82-11.15 (m, 2 H), 12.33-12.89 (m, 2 H) 1b-23  0.67-0.94 (m,26H), 1.16-1.76 (m, 16 H), 2.65-3.09 (m, 16 H), 4.39-5.72 (m, 12 H),6.24-6.26 (m, 2 H), 7.14 (d, 4 H), 7.27 (dd, 4 H), 7.43-7.45 (m, 2 H),7.74-7.77 (m, 2H) 1b-24  0.67-0.96 (m, 26H), 1.17-1.74 (m, 16 H), 1.98(s, 6H), 2.64-3.07 (m, 16 H), 4.39- 5.71 (m, 12 H), 7.13 (d, 4 H),7.21-7.30 (m, 6 H), 7.47-7.50 (m, 2H) 1b-25  0.67-0.96 (m, 26H),1.19-1.76 (m, 16 H), 2.65-3.09 (m, 16 H), 4.39-5.74 (m, 12 H), 7.19 (d,4 H), 7.29 (dd, 4 H), 7.54-7.56 (m, 2 H), 8.01-8.03 (m, 2H) 1b-26 0.65-0.96 (m, 26H), 1.14-1.74 (m, 16 H), 2.65-3.09 (m, 16 H), 4.38-5.74(m, 12 H), 7.14-7.35 (m, 14 H), 7.54 (d, 4 H), 7.87-7.91 (m, 2 H),8.20-8.24 (m, 2H) 1b-27  0.64-0.97 (m, 26H), 1.14-1.74 (m, 16 H),2.63-3.10 (m, 16 H), 4.38-5.73 (m, 12 H), 7.15-7.34 (m, 12 H), 7.53-7.59(m, 4 H), 7.85-7.89 (m, 2 H), 8.18-8.24 (m, 2H) 1b-28  0.65-0.94 (m,26H), 1.14-1.72 (m, 16 H), 2.64-3.12 (m, 16 H), 4.38-5.73 (m, 12 H),7.18-7.31 (m, 8 H), 7.39 (d, 4 H), 7.58 (dd, 4 H), 7.89-7.92 (m, 2H),8.25-8.29 (m, 2 H) 1b-29  0.68-0.95 (m, 26H), 1.19-1.74 (m, 16 H),2.05-2.15 (m, 12 H), 2.66-3.08 (m, 16 H), 4.38-5.71 (m, 12 H), 5.85 (s,2 H), 7.01 (d, 4 H), 7.26 (dd, 4 H) 1b-30  0.67-0.95 (m, 26H), 1.17-1.74(m, 34 H), 2.64-3.07 (m, 16 H), 4.38-5.73 (m, 12 H), 7.14 (d, 4 H),7.23-7.34 (m, 6 H), 7.53-7.56 (m, 2H) 1b-31  0.65-0.95 (m, 26H), 1.11(t, 6 H), 1.18-1.74 (m, 16 H), 2.40 (q, 4H), 2.65-3.08 (m, 16 H),4.39-5.71 (m, 12 H), 7.14 (d, 4 H), 7.24-7.30 (m, 6 H), 7.50-7.53 (m,2H) 1b-32  0.71-0.92 (m, 26 H), 1.27-1.69 (m, 16 H), 2.67-3.04 (m, 16H), 3.97 (s, 2 H) 4.39- 4.48 (m, 1 H), 5.09-5.69 (m, 11 H), 7.17-7.19(m, 4 H), 7.28-7.30 (m, 4 H), 7.62 (s, 2 H), 8.09 (br s, 2 H) 1b-34  1HNMR (400 MHz, CDCl₃) δ: 0.83-0.93 (m, 20 H), 1.24-1.70 (m, 20 H), 2.64-3.09 (m, 18 H), 4.41-4.43 (m, 1 H), 5.27-5.61 (m, 11 H), 7.19-7.25 (m, 8H), 7.52- 7.78 (m, 4 H) 1b-35  0.67-0.95 (m, 26H), 1.17-1.73 (m, 16 H),2.67-3.08 (m, 16 H), 4.39-5.72 (m, 12 H), 7.19 (d, 4 H), 7.29 (d, 4 H),7.52-7.55 (m, 2H), 8.02-8.04 (m, 2 H) 1b-36  0.67-0.95 (m, 26H),1.20-1.73 (m, 16 H), 1.84 (s, 6 H), 2.04-2.08 (m, 12 H), 2.67- 3.07 (m,16 H), 4.38-5.70 (m, 12 H), 7.02 (d, 4 H), 7.26 (d, 4 H) 1b-37 0.67-0.96 (m, 26H), 1.14 (d, 12 H), 1.22-1.76 (m, 16 H), 2.67-3.06 (m,18 H), 4.39- 5.72 (m, 12 H), 7.14 (d, 4 H), 7.25-7.32 (m, 8 H),7.51-7.53 (m, 2 H) 1b-38  0.66-0.94 (m, 26H), 1.18-1.74 (m, 16 H), 2.34(s, 6 H), 2.67-3.08 (m, 16 H), 4.39- 5.72 (m, 12 H), 7.23 (d, 4 H), 7.30(d, 4 H), 7.91-7.93 (m, 2 H), 8.47-8.49 (m, 2 H). 1b-39  0.67-0.95 (m,26H), 1.19-1.76 (m, 22 H), 2.67-3.08 (m, 16 H), 4.19 (q, 4 H), 4.38-5.72 (m, 12 H), 7.23 (d, 4 H), 7.30 (d, 4 H), 7.83-7.85 (m, 2 H),8.39-8.41 (m, 2 H) 1b-40  0.67-0.95 (m, 26H), 1.19-1.76 (m, 16 H),2.67-3.08 (m, 16 H), 3.55-3.61 (m, 16 H), 4.39-5.72 (m, 12 H), 7.21 (d,4 H), 7.29 (d, 4 H), 7.69-7.71 (m, 2 H), 8.19-8.21 (m, 2H) 1b-41 0.67-0.94 (m, 26H), 1.19-1.94 (m, 24 H), 2.67-3.07 (m, 16 H), 3.41 (t, 4H), 3.61 (t, 4 H), 4.39-5.72 (m, 12 H), 7.21 (d, 4 H), 7.29 (d, 4 H),7.77-7.79 (m, 2 H), 8.26-8.28 (m, 2 H). 1b-42  0.67-0.94 (m, 26H),1.19-1.75 (m, 28 H), 2.67-3.08 (m, 16 H), 3.51-3.54 (m, 8 H), 4.39-5.72(m, 12 H), 7.21 (d, 4 H), 7.29 (d, 4 H), 7.63-7.65 (m, 2 H), 8.11-8.13(m, 2 H) 1b-43  0.67-0.96 (m, 26H), 1.19-1.76 (m, 16 H), 2.08 (s, 6 H),2.67-3.07 (m, 16 H), 4.39- 5.72 (m, 12 H), 7.19 (d, 4 H), 7.28 (d, 4 H),7.92-7.94 (m, 2 H). 1b-44  0.68-0.96 (m, 26H), 1.19-1.76 (m, 16 H),2.08-2.13 (m, 12 H), 2.67-3.07 (m, 16 H), 4.39-5.70 (m, 12 H), 7.06 (d,4 H), 7.28 (d, 4 H) 1b-45  0.41-0.44 (m, 4 H), 0.67-0.98 (m, 30 H),1.23-1.74 (m, 18 H), 2.68-3.04 (m, 16 H), 4.39-4.45 (m, 1 H), 5.01-5.73(m, 11 H), 7.12-7.15 (m, 4 H), 7.22-7.27 (m, 6 H), 7.49-7.51 (m, 2 H)1b-46  0.67-0.94 (m, 27 H), 1.24-1.68 (m, 15 H), 2.67-3.12 (m, 16 H),4.39-4.43 (m, 1 H), 5.02-5.71 (m, 13 H), 7.17-7.19 (m, 4 H), 7.28-7.29(m, 4 H), 7.52 (brs, 2 H), 7.95-7.60 (m, 2 H) 1b-47  0.65-0.94 (m, 30H), 1.20-1.73 (m, 21 H), 2.33-2.36 (m, 4 H), 2.67-3.02 (m, 16 H),4.37-4.48 (m, 1 H), 5.01-5.69 (m, 12 H), 7.11-7.13 (m, 4 H), 7.26 (s, 6H), 7.50 (s, 2 H) 1b-48  0.74-1.00 (m, 26 H), 1.21-1.69 (m, 20 H),2.03-2.06 (m, 12 H), 2.25-2.30 (m, 5 H), 2.67-2.89 (m, 12 H), 3.01-3.05(m, 4 H), 4.41-4.43 (m, 1 H), 5.08-5.68 (m, 12 H), 6.98-7.00 (m, 4 H),7.24-7.26 (m, 4 H) 1b-49  0.67-0.94 (m, 26H), 1.18-1.76 (m, 28 H),2.67-3.08 (m, 24 H), 4.39-5.73 (m, 12 H) 7.22 (d, 4 H), 7.31 (d, 4 H),7.77-7.79 (m, 2 H), 8.44-8.46 (m, 2H) 1b-50  0.68-0.94 (m, 26H),1.19-1.76 (m, 16 H), 2.67-3.09 (m, 24 H), 3.64-3.67 (m, 8 H), 4.39-5.73(m, 12 H), 7.24 (d, 4H), 7.32 (d, 4H), 7.81-7.83 (m, 2 H), 8.49-8.51 (m,2H) 1b-51  0.78-0.93 (m, 24 H), 1.23-1.69 (m, 17 H), 2.09-2.11 (m, 12H), 2.67-3.02 (m, 16 H), 4.39-4.41 (m, 1 H), 5.01-5.68 (m, 12 H),7.04-7.06 (d, J = 7.2 Hz 4 H), 7.26-7.28 (d, J = 7.2 Hz, 4 H) 1b-52 0.66-0.94 (m, 24 H), 1.20-1.70 (m, 16 H), 2.67-3.03 (m, 16 H), 3.62 (s,6 H), 4.39-4.42 (m, 1 H), 5.01-5.69 (m, 13 H), 7.07-7.52 (m, 12 H)1b-53  1H NMR (400 MHz, CDCl₃) δ: 0.72-0.1.01 (m, 28 H), 1.02-1.47 (m,12 H), 1.60- 1.74 (m, 4 H), 2.73-3.17 (m, 18 H), 3.63 (s, 1 H),4.42-4.45 (m, 1 H), 5.05-5.98 (m, 14 H), 7.15-7.23 (m, 8 H), 7.71-7.79(m, 4 H) 1b-54  0.67-0.94 (m, 26H), 1.18-1.73 (m, 24 H), 2.67-3.11 (m,24 H), 4.39-5.73 (m, 12 H), 7.21 (d, 4 H), 7.31 (d, 4 H), 7.86 (s, 2 H),8.50-8.52 (m, 2H) 1b-55  0.69-0.94 (m, 24 H), 1.01-1.16 (m, 12 H),1.29-1.36 (m, 12 H), 1.38-1.71 (m, 12 H), 2.66-3.01 (m, 24 H), 4.40-4.42(m, 1 H), 5.01-5.66 (m, 13 H), 5.93 (s, 2 H), 6.97-6.99 (m, 4 H),7.24-7.27 (m, 4 H) 1b-56  0.67-0.94 (m, 24 H), 1.25-1.80 (m, 16 H),2.67-3.04 (m, 28 H), 4.40-4.42 (m, 1 H), 5.01-5.90 (m, 13 H), 7.20-7.30(m, 8 H), 7.72 (s, 2 H), 8.20 (s, 2 H) 1b-57  0.79-0.94 (m, 30 H),1.23-1.70 (m, 20 H), 2.03-2.05 (m, 12 H), 2.24 (t, J = 6.2 Hz, 4 H),2.67-3.01 (m, 16 H), 4.39-4.42 (m, 1 H), 5.10-5.67 (m, 13 H), 6.96- 6.98(m, 4 H), 7.24-7.25 (m, 4 H) 1b-58  0.69-0.92 (m, 24 H), 1.23-1.69 (m,16 H), 2.32 (s, 6 H), 2.40 (s, 6 H), 2.67- 3.09 (m, 16 H), 4.39-4.42 (m,1 H), 5.09-5.69 (m, 13 H), 7.13-7.15 (m, 4 H), 7.25- 7.39 (m, 4 H)1b-59  0.71-0.94 (m, 24 H), 1.23-1.70 (m, 16 H), 2.67-3.04 (m, 16 H),3.18 (s, 6 H), 4.39-4.42 (m, 1 H), 5.08-571 (m, 13 H), 7.25-7.32 (m, 8H), 7.91 (s, 2 H), 8.49- 8.50 (m, 2 H) 1b-60  0.76-0.94 (m, 24 H),1.12-1.13 (m, 12 H), 1.23-1.69 (m, 18 H), 2.67-3.03 (m, 16 H), 4.38-4.41(m, 1 H), 5.10-5.70 (m, 13 H), 7.14-7.16 (m, 4 H), 7.27-7.29 (m, 4 H),7.46 (s, 2 H), 7.91 (s, 2 H) 1b-61  0.67-0.95 (m, 26H), 1.19-1.73 (m, 16H), 1.96-2.01 (m, 4 H), 2.67-3.07 (m, 16 H), 3.61-3.63 (m, 8 H),4.39-5.73 (m, 12 H), 7.24 (d, 4 H), 7.32 (d, 4 H), 7.92 (s, 2 H),8.58-8.60 (m, 2H) 1b-62  0.68-0.97 (m, 26H), 1.18-1.72 (m, 16 H),2.67-3.07 (m, 16 H), 4.39-5.71 (m, 12 H), 7.00 (t, 2 H), 7.20 (d, 4 H),7.30 (d, 4 H), 7.68 (s, 2 H), 8.14-8.16 (m, 2H) 1b-63  0.68-0.96 (m,26H), 1.19-1.72 (m, 16 H), 2.67-3.07 (m, 16 H), 4.39-5.72 (m, 12 H),6.37-6.39 (m, 2 H), 7.19 (d, 4 H), 7.29 (d, 4 H), 7.84-7.86 (m, 2H)1b-64  0.68-0.94 (m, 26H), 1.18-1.72 (m, 16 H), 2.67-3.07 (m, 16 H),4.39-5.71 (m, 12 H), 6.45-6.47 (m, 2 H), 7.17-7.20 (m, 4 H), 7.29-7.32(m, 4 H), 7.73-7.75 (m, 2H) 1b-65  0.67-0.94 (m, 24 H), 1.21-1.70 (m, 16H), 2.04-2.05 (m, 12 H), 2.43 (t, J = 7.3 Hz, 4 H), 2.67-3.01 (m, 16 H),3.35-3.37 (m, 4 H), 4.39-4.41 (m, 1 H), 4.53- 4.56 (m, 2 H), 5.08-5.68(m, 13 H), 6.99-7.01 (m, 4 H), 7.24-7.26 (m, 4 H) 1b-66  0.67-0.93 (m,26 H), 1.23-1.78 (m, 16 H), 2.69-3.12 (m, 16 H), 4.39-4.42 (m, 1 H),4.91-5.71 (m, 11 H), 7.22-7.24 (m, 4 H), 7.35-7.38 (m, 4 H), 7.98 (s, 2H) 1b-67  0.54-0.59 (m, 4 H), 0.68-0.96 (m, 30H), 1.17-1.84 (m, 18 H),2.67-3.07 (m, 16 H), 4.39-5.70 (m, 12 H), 5.92 (s, 2 H), 7.12 (d, 4 H),7.26 (d, 4 H), 7.59 (s, 2H) 1b-68  0.67-0.96 (m, 26H), 1.18-1.76 (m, 16H), 2.63-3.07 (m, 16 H), 4.38-5.72 (m, 12 H), 6.71-6.73 (m, 2 H),7.20-7.40 (m, 14 H), 7.76 (d, 4 H), 7.84-7.86 (m, 2H) 1b-69  0.67-0.94(m, 26H), 1.17-1.76 (m, 16 H), 2.67-3.08 (m, 16 H), 4.38-5.73 (m, 12 H),6.72 (s, 2 H), 7.22 (d, 4 H), 7.31 (d, 4 H), 8.06 (s, 2H) 1b-70 0.66-0.93 (m, 24 H), 1.20-1.70 (m, 17 H), 2.67-3.08 (m, 16 H), 4.35-4.45(m, 1 H), 5.01-5.71 (m, 12 H), 7.28-7.33 (m, 8 H), 8.26 (s, 2 H),8.99-9.00 (m, 2 H) 1b-71  0.67-0.93 (m, 24 H), 1.17-1.67 (m, 17 H),2.65-3.04 (m, 16 H), 4.37-4.43 (m, 1 H), 5.06-5.70 (m, 12 H), 7.14-7.15(m, 2 H), 7.17-7.23 (m, 4 H), 7.25-7.31 (m, 4 H), 7.61-7.63 (m, 2 H),7.72-7.75 (m, 2 H), 8.01-8.02 (m, 2 H), 8.33-8.34 (m, 2 H), 8.47-8.48(m, 2 H) 1b-72  0.67-0.94 (m, 24 H), 1.23-1.70 (m, 17 H), 1.94 (s, 6 H),2.67-3.03 (m, 16 H), 4.41-4.43 (m, 1 H), 5.07-5.72 (m, 12 H), 7.13-7.15(m, 4 H), 7.17-7.18 (m, 1 H), 7.26-7.27 (m, 3 H), 7.36 (s, 2 H),7.89-7.90 (m, 2 H), 9.91 (s, 2 H) 1b-74  0.44-0.48 (m, 4 H), 0.62-0.94(m, 28 H), 1.21-1.69 (m, 17 H), 2.67-3.04 (m, 18 H), 4.37-4.48 (m, 1 H),5.02-5.70 (m, 12 H), 7.18-7.30 (m, 8 H), 7.81-8.14 (m, 6H) 1b-75 0.67-0.94 (m, 26 H), 1.21-1.70 (m, 17 H), 2.67-3.03 (m, 18 H), 3.46-3.51(m, 4 H), 4.37-4.45 (m, 1 H), 4.58 (t, J = 5.2 Hz, 2 H), 5.08-5.69 (m,12 H), 7.13-7.15 (m, 4 H), 7.25-7.27 (m, 6 H), 7.52 (brs, 2 H 1b-76 0.60-0.95 (m, 24 H), 1.15-1.80 (m, 18 H), 2.65-3.20 (m, 22 H), 4.35-4.45(m, 1 H), 5.00-5.80 (m, 11 H), 7.10-7.35 (m, 10 H), 7.69 (s, 2 H), 9.11(s, 2 H) 1b-77  0.66-0.96 (m, 26H), 1.14-1.73 (m, 16 H), 2.64-3.11 (m,16 H), 4.38-5.80 (m, 12 H), 7.41 (d, 4 H), 7.57-7.60 (m, 4 H), 8.12-8.15(m, 2H), 8.39 (s, 4 H), 8.80 (d, 2 H), 8.93-8.97 (m, 2 H), 9.58 (s, 2 H)1b-78  0.67-0.95 (m, 26H), 1.17-1.73 (m, 28 H), 1.89-1.96 (m, 4 H),2.67-3.07 (m, 18 H), 4.39-5.71 (m, 12 H), 7.14 (d, 4 H), 7.24-7.30 (m, 6H), 7.51-7.53 (m, 2H) 1b-79  0.67-0.95 (m, 26 H), 1.15-1.73 (m, 28 H),2.67-3.07 (m, 18 H), 4.39-5.71 (m, 12 H), 6.06 (s, 2 H), 7.12 (d, 4 H),7.26 (d, 4 H), 7.59 (s, 2H) 1b-80  0.68-0.94 (m, 26H), 1.20-1.76 (m, 24H), 2.29 (s, 6 H), 2.39 (s, 6 H), 2.67-3.09 (m, 24 H), 4.39-5.71 (m, 12H), 7.06 (d, 4 H), 7.30 (d, 4 H) 1b-81  0.67-0.94 (m, 26H), 1.19-1.74(m, 34 H), 2.67-3.07 (m, 16 H), 4.39-5.71 (m, 12 H), 6.10 (s, 2 H), 7.11(d, 4 H), 7.26 (d, 4 H), 7.55-7.57 (m, 2H) 1b-82  0.68-0.93 (m, 24 H),1.25-1.89 (m, 16 H), 2.65-3.03 (m, 16 H), 4.38-4.40 (m, 1 H), 5.02-5.67(m, 13 H), 6.60 (brs, 2 H), 7.20-7.29 (m, 8 H), 7.43-7.44 (m, 2 H), 7.55(brs, 2 H), 7.71 (s, 2 H), 7.79 (s, 2 H) 1b-83  0.65-0.95 (m, 24 H),1.02-1.75 (m, 18 H), 2.65-3.05 (m, 16 H), 4.30-4.45 (m, 8 H), 4.85-5.75(m, 16 H), 6.14 (s, 2 H), 7.05-7.10 (m, 4H), 7.25-7.30 (m, 4H) 1b-84 0.65-0.98 (m, 24 H), 1.20-1.80 (m, 18 H), 1.98-2.00 (m, 18 H), 2.60-3.10(16 H), 4.38-4.42 (m, 1 H), 4.85-5.60 (m, 11 H), 7.00 (d, J = 7.8 Hz, 4H), 7.28 (d, J = 7.0 Hz, 4 H) 8.95 (s, 2 H) 1b-85  0.69-0.94 (m, 26H),1.19-1.76 (m, 28 H), 2.27 (s, 6 H), 2.36 (s, 6 H), 2.67-3.09 (m, 24 H),4.39-5.71 (m, 12 H), 7.06 (d, 4 H), 7.30 (d, 4 H) 1b-86  0.72-0.91 (m,24 H), 1.15-1.80 (m, 17 H), 2.65-3.05 (m, 16 H), 4.41-4.45 (m, 1 H),5.00-5.70 (m, 12 H), 7.24-7.36 (m, 8 H), 7.71-7.73 (m, 2 H), 8.18-8.21(m, 2 H), 8.57-8.60 (m, 2 H), 8.67-8.69 (m, 2 H), 9.03 (s, 2 H) 1b-87 0.72-0.92 (m, 24 H), 1.19-1.67 (m, 16 H), 2.65-3.04 (m, 16 H), 4.35-4.45(m, 2 H), 5.01-5.75 (m, 12 H), 7.24-7.31 (m, 8 H), 8.14 (s, 2 H), 8.40(s, 2 H), 8.49- 8.53 (m, 4 H), 8.96 (s, 2 H) 1b-88  0.65-0.94 (m, 24 H),1.23-1.70 (m, 17 H), 1.79 (s, 6 H), 2.68-3.03 (m, 16 H), 4.04 (d, J =5.4 Hz, 4 H), 4.35-4.45 (m, 1 H), 5.01-5.75 (m, 12 H), 7.15-7.17 (m, 4H), 7.26-7.28 (m, 4 H), 7.33 (s, 2 H), 7.62 (s, 2 H), 8.09 (brs, 2 H)1b-89  0.67-0.93 (m, 24 H), 1.23-1.79 (m, 16 H), 2.66-3.04 (m, 16 H),3.85-3.95 (m, 1 H), 4.35-4.45 (m, 1 H), 5.01-5.75 (m, 12 H), 6.89-7.5(m, 14 H) 1b-90  0.69-0.94 (m, 24 H), 1.15-1.75 (m, 17 H), 2.67-3.04 (m,16 H), 4.35-4.45 (m, 1 H), 5.01-5.75 (m, 12 H), 6.97 (s, 2 H), 7.18-7.31(m, 8 H), 7.51 (s, 2 H), 7.83 (s, 2 H), 8.14-8.15 (s, 2 H) 1b-91 0.67-0.94 (m, 24 H), 1.20-1.75 (m, 35 H), 2.68-3.02 (m, 16 H), 3.92-3.94(m, 4 H), 4.35-4.45 (m, 1 H), 5.01-5.69 (m, 12 H), 7.11-7.15 (m, 6 H),7.25-7.32 (m, 6 H), 7.57-7.58 (m, 2 H) 1b-92  0.70-0.95 (m, 24 H),1.23-1.71 (m, 16 H), 2.26 (s, 6 H), 2.34 (s, 6 H), 2.67-3.03 (m, 16 H),4.41-4.43 (m, 1 H), 5.03-5.76 (m, 13 H), 7.07-7.18 (m, 8 H), 7.28- 7.30(m, 4 H) 1b-94  0.66-0.92 (m, 24 H), 1.21-1.68 (m, 16 H), 2.10 (s, 6 H),2.65-3.00 (m, 16 H), 4.37-4.40 (m, 1 H), 5.01-5.67 (m, 13 H), 5.98 (s, 2H), 7.10-7.12 (m, 4 H), 7.23- 7.25 (m, 4 H), 7.59 (s, 2 H) 1b-95 0.71-0.93 (m, 24 H), 1.09-1.70 (m, 22 H), 2.67-3.02 (m, 20 H), 4.39-4.41(m, 1 H), 5.01-5.66 (m, 13 H), 6.05 (s, 2 H), 7.12-7.14 (m, 4 H),7.24-7.26 (m, 4 H), 7.61 (s, 2 H) 1b-96  0.69-0.94 (m, 24 H), 1.24-1.69(m, 16 H), 2.67-3.03 (m, 16 H), 4.39-4.41 (m, 1 H), 5.01-5.67 (m, 13 H),6.44 (s, 2 H), 7.06-7.08 (m, 4 H), 7.26-7.28 (m, 4 H) 7.58 (s, 2 H)1b-97  0.75-0.95 (m, 24 H), 1.27-1.70 (m, 16 H), 2.67-3.02 (m, 16 H),4.35-4.37 (m, 4 H), 4.94-5.70 (m, 16 H), 6.18 (brs, 2 H), 7.14-7.16 (m,4 H), 7.26-7.28 (m, 4 H) 7.67 (brs, 2 H) 1b-98  0.67-0.95 (m, 24 H),1.19-1.70 (m, 17 H), 2.68-3.03 (m, 16 H), 3.86-3.87 (m, 4 H), 4.40-4.43(m, 1 H), 5.07-5.71 (m, 12 H), 7.17-7.28 (m, 8 H), 7.54 (s, 2 H), 7.85(s, 2 H), 8.08 (brs, 6 H) 1b-99  0.86-0.94 (m, 24 H), 1.23-1.67 (m, 18H), 1.94 (s, 6 H), 2.67-3.03 (m, 16 H), 4.40-4.42 (m, 1 H), 5.01-5.69(m, 11 H), 6.45 (s, 2 H), 7.15-7.17 (m, 4 H), 7.26- 7.28 (m, 4 H), 7.64(brs, 2 H), 10.36 (s, 2 H) 1b-100 0.72-0.93 (m, 24 H), 1.08-1.33 (m, 12H), 1.46 (s, 18 H), 1.61-1.92 (m, 4 H), 2.66-3.02 (m, 16 H), 4.40-4.42(m, 1 H), 5.02-5.66 (m, 13 H), 6.83 (s, 2 H), 7.01- 7.03 (m, 4 H),7.25-7.26 (m, 4 H), 7.58 (s, 2 H) 1b-101 0.70-0.95 (m, 24 H), 1.23-1.68(m, 17 H), 2.68-3.05 (m, 16 H), 4.40-4.43 (m, 1 H), 5.03-5.68 (m, 12 H),7.24-7.30 (m, 12 H), 7.71 (s, 2 H), 8.25 (brs, 2 H) 1b-102 0.68-0.94 (m,24 H), 1.23-1.70 (m, 16 H), 2.67-3.07 (m, 16 H), 4.38-4.40 (m, 1 H),5.04-5.74 (m, 13 H), 7.20-7.46 (m, 18 H), 7.71 (brs, 2 H), 8.15-8.17 (m,2 H) 1b-103 0.67-0.93 (m, 24 H), 1.23-1.70 (m, 16 H), 2.67-3.09 (m, 16H), 4.41-4.43 (m, 1 H), 5.03-5.71 (m, 13 H), 6.98 (s, 2 H), 7.22-7.24(m, 4 H), 7.30-7.32 (m, 4 H), 8.13 (s, 2 H) 1b-104 0.66-0.94 (m, 24 H),1.23-1.57 (m, 22 H), 2.67-3.10 (m, 16 H), 4.08 (q, J = 6.8 Hz, 4 H),4.41-4.43 (m, 1 H), 5.05-5.70 (m, 13 H), 6.96 (s, 1 H), 7.04-7.09 (m, 5H), 7.21-7.26 (m, 6 H) 1b-105 0.70-0.94 (m, 24 H), 1.23-1.69 (m, 15 H),2.67-3.02 (m, 24 H), 3.65 (brs, 8 H), 4.40-4.42 (m, 1 H), 5.02-5.73 (m,14 H), 7.10-7.12 (m, 5 H), 7.24-7.25 (m, 5 H), 7.54 (brs, 2 H) 1b-1060.68-0.93 (m, 26 H), 1.27-2.19 (m, 27 H), 2.67-3.02 (m, 16 H), 3.46-3.49(m, 2 H), 4.40-4.42 (m, 1 H), 4.94-5.86 (m, 12 H), 6.12 (brs, 2 H),7.12-7.14 (m, 4 H), 7.26-7.27 (m, 4 H), 7.62 (brs, 2 H) 1b-107 0.72-0.93(m, 24 H), 1.26-1.75 (m, 16 H), 2.66-3.04 (m, 16 H), 4.03 (s, 6 H),4.38-4.41 (m, 1 H), 5.03-5.6.8 (m, 13 H), 7.12-7.23 (m, 4 H), 7.29-7.30(m, 4 H), 7.76 (s, 2 H), 8.09-8.14 (m, 4 H) 1b-108 0.50-0.55 (m, 4 H),0.68-0.94 (m, 30H), 1.18-1.79 (m, 18 H), 2.67-3.06 (m, 16 H), 4.38-5.70(m, 12 H), 5.90 (s, 2 H), 7.06 (d, 4 H), 7.26 (d, 4 H), 7.32 (s, 2H)1b-109 0.56-1.02 (m, 26 H) 1.04-1.84 (m, 16 H) 2.27 (m, 4 H) 2.55-3.11(m, 16 H) 3.42- 3.66 (m, 2 H) 3.75 (m, 4 H) 4.13 (m, 4 H) 4.41 (m, 1 H)4.92-5.77 (m, 9 H) 5.96 (m, 2 H) 7.01-7.42 (m, 8 H) 7.60 (m, 2H), 7.83(m, 2 H) 1b-110 0.70-0.94 (m, 24 H), 1.24-1.69 (m, 16 H), 2.08-2.09 (m,12 H), 2.67-3.02 (m, 16 H), 4.40-4.42 (m, 1 H), 5.03-5.68 (m, 13H),7.02-7.04 (m, 4H), 7.25-7.27 (m, 4 H) 1b-111 0.72-0.92 (m, 24 H),1.16-1.69 (m, 16 H), 2.66-3.03 (m, 16 H), 4.38-4.41 (m, 1 H), 5.01-5.67(m, 13 H), 6.48 (brs, 2 H), 6.75 (s, 2 H), 7.17-7.18 (m, 4 H), 7.27-7.29 (m, 4 H), 7.67 (s, 2 H), 7.78 (s, 2 H), 7.98 (s, 2 H) 1b-1120.69-0.93 (m, 26 H), 1.14-1.69 (m, 27 H), 2.67-3.03 (m, 16 H), 4.38-4.41(m, 1 H), 5.02-5.69 (m, 14 H), 7.15-7.17 (m, 4 H), 7.27-7.29 (m, 4 H),7.51 (brs, 2 H), 7.94 (brs, 2 H) 1b-113 0.62-0.94 (m, 32 H), 1.23-1.69(m, 18 H), 2.67-3.04 (m, 16 H), 4.39-4.41 (m, 1 H), 5.03-5.69 (m, 13 H),7.14-7.16 (m, 4 H), 7.27-7.29 (m, 4 H), 7.50 (s, 2 H), 7.93-7.94 (m, 2H) 1b-114 0.68-0.94 (m, 26 H), 1.23-1.69 (m, 33 H), 2.67-3.04 (m, 16 H),4.42-4.44 (m, 1 H), 5.09-5.69 (m, 12 H), 7.15-7.17 (m, 4 H), 7.27-7.29(m, 4 H), 7.49-7.50 (m, 2 H), 7.92-7.93 (m, 2 H) 1b-115 0.67-0.94 (m, 24H), 1.24-1.69 (m, 17 H), 2.67-3.06 (m, 16 H), 3.82 (s, 6 H), 4.38-4.41(m, 1 H), 5.05-5.68 (m, 14 H), 7.02-7.04 (m, 4 H), 7.25-7.27 (m, 6 H)1b-116 0.60-1.04 (m, 26H), 1.04-1.84 (m, 20H), 2.58-3.15 (m, 16H),3.37-3.45 (m, 4H), 3.79-3.91 (m, 4H), 4.35-4.59 (m, 1H), 4.97-5.79 (m,11H), 7.02-7.35 (m, 8H), 7.50- 7.72 (m, 2H), 7.50-7.72 (m, 2H) 1b-1170.69-0.93 (m, 23 H), 1.23-1.83 (m, 19 H), 2.21-2.32 (m, 12 H), 2.67-3.18(m, 16 H), 4.35-4.45 (m, 1 H), 5.09-5.67 (m, 11 H), 7.11 (d, J = 7.5 Hz,4 H), 7.29 (d, J = 6.9 Hz, 4 H) 1b-118 0.67-0.94 (m, 26 H), 1.20-1.70(m, 16 H), 1.96 (s, 6 H), 2.67-3.04 (m, 16 H), 4.35-4.45 (m, 1 H),5.00-5.75 (m, 11 H), 7.15-7.96 (m, 12 H) 1b-119 0.67-0.94 (m, 26 H),1.10 (t, J = 7.4 Hz, 6 H,), 1.21-1.75 (m, 16 H), 2.31-2.37 (m, 4 H),2.67-3.04 (m, 16 H), 4.35-4.45 (m, 1 H), 5.00-5.75 (m, 11 H), 7.15- 7.96(m, 12 H) 1b-120 0.66-0.92 (m, 26 H), 1.15-1.70 (m, 16 H), 2.64-3.03 (m,16 H), 4.35-4.45 (m, 1 H), 5.01-5.72 (m, 11 H), 6.82 (s, 2 H), 7.22-8.55(m, 18 H) 1b-121 0.66-0.92 (m, 26 H), 1.23-1.72 (m, 16 H), 2.66-3.05 (m,16 H), 4.35-4.45 (m, 1 H), 5.01-5.71 (m, 11 H), 7.06-8.14 (m, 12 H)1b-122 0.70-1.78 (m, 60 H), 2.42-2.45 (m, 2 H), 2.67-3.03 (m, 16 H),4.41-4.45 (m, 1 H), 5.01-5.69 (m, 11 H), 7.08-7.09 (m, 4 H), 7.28-7.29(m, 4 H) 1b-123 0.73-0.84 (m, 28 H), 0.92-0.96 (m, 12 H), 1.10-1.84 (m,14 H), 2.65-3.03 (m, 24 H), 4.40-4.45 (m, 1 H), 5.00-5.67 (m, 11 H),7.17 (bs, 4H), 7.31 (bs, 4 H) 1b-126 0.70-0.94 (m, 26 H), 1.07 (d, 12H), 1.22-1.76 (m, 16 H), 2.66-3.06 (m, 18 H), 4.39- 5.69 (m, 12 H), 6.11(s, 2 H), 7.00 (d, 4 H), 7.24-7.27 (m, 4 H), 7.38 (s, 2 H) 1b-1270.67-0.96 (m, 26 H), 1.22-1.76 (m, 34 H), 2.66-3.05 (m, 16 H), 4.39-5.67(m, 12 H), 6.09 (s, 2 H), 6.88 (d, 4 H), 7.23-7.26 (m, 4 H), 7.38 (s,2H) 1b-128 0.63-0.94 (m, 26 H), 1.22-1.76 (m, 16 H), 2.66-3.04 (m, 16H), 4.39-5.68 (m, 12 H), 6.46 (s, 2 H), 6.88 (d, 4 H), 7.22-7.26 (m, 4H), 7.39-7.42 (m, 10 H), 7.58 (s, 2 H) 1b-129 0.67-0.96 (m, 26 H),1.22-1.92 (m, 24 H), 2.13-2.17 (m, 4 H), 2.65-3.05 (m, 16 H), 3.44-3.47(m, 2 H), 4.39-5.67 (m, 12 H), 6.20 (s, 2 H), 6.97 (d, 4 H), 7.24-7.27(m, 4 H), 7.38 (s, 2 H) 1b-130 0.67-0.91 (m, 25 H), 1.23-1.67 (m, 17 H),2.20 (s, 6 H), 2.27 (s, 6 H), 2.67-3.03 (m, 16 H), 4.40-4.45 (m, 1 H),5.08-5.69 (m, 11 H), 7.08-7.09 (m, 4 H), 7.28- 7.30 (m, 4 H) 1b-1330.65-0.95 (m, 30 H), 1.11 (t, J = Hz, 6 H), 1.21-1.72 (m, 18 H),2.42-2.45 (m, 8 H), 2.66-3.00 (m, 16H), 4.35-4.45 (m, 1H), 5.01-5.68 (m,15 H), 6.94-7.23 (m, 8 H) 1b-134 0.67-0.93 (m, 26 H), 1.15-1.72 (m, 16H), 2.63-3.09 (m, 16 H), 3.76 (s, 6 H), 4.39- 5.72 (m, 12 H), 6.62 (s, 2H), 6.89-6.96 (m, 4 H), 7.19-7.31 (m, 8 H), 7.68 (d, 4 H), 7.79 (s, 2 H)1b-136 0.67-0.94 (m, 28 H), 1.18-1.37 (m, 8 H), 1.42-1.63 (m, 5 H),1.65-1.72 (m, 2 H), 2.10 (s, 6 H), 2.68 (s, 2 H), 2.75 (d, 4 H), 2.85(s, 2 H), 2.91 (br d, 5 H), 3.00-3.11 (m, 3 H), 4.16-4.44 (m, 1 H),5.00-5.24 (m, 4 H), 5.30-5.54 (m, 6 H), 5.65-5.74 (m, 1 H), 7.23 (d, 4H), 7.31 (br d, 4 H), 7.91 (s, 2 H) 1b-138 0.66-0.92 (m, 26 H),1.00-1.74 (m, 16 H), 2.64-3.03 (m, 16 H), 4.35-4.45 (m, 1 H), 5.00-5.72(m, 11 H), 6.92 (s, 2 H), 7.21-8.55 (m, 18 H) 1b-139 0.66-0.92 (m, 26H), 1.00-1.74 (m, 16 H), 2.64-3.03 (m, 16 H), 4.35-4.45 (m, 1 H),5.00-5.72 (m, 11 H), 6.92 (s, 2 H), 7.21-8.55 (m, 18 H) 1b-140 0.60-1.01(m, 26H), 1.12-1.87 (m, 16H), 2.58-3.16 (m, 16H), 4.33-4.52 (m, 2H),4.93-5.81 (m, 12H), 7.07-7.35 (m, 8H), 7.37-7.49 (m, 2H), 7.74-8.00 (m,2H) 1b-141 0.57-1.00 (m, 26H), 1.11-1.78 (m, 16H), 1.86-2.09 (m, 4H),2.20-2.40 (m, 4H), 2.63- 3.16 (m, 16H), 4.24-4.53 (m, 5H), 4.96-5.83 (m,12H), 7.02-7.34 (m, 8H), 7.37-7.57 (m, 2H) 1b-142 0.58-1.01 (m, 26H),1.07-1.92 (m, 16H), 2.62-3.16 (m, 16H), 4.36-4.55 (m, 5H), 4.71-4.92 (m,4H), 4.92-5.79 (m, 14H), 7.04-7.37 (m, 10H), 7.47-7.57 (m, 2H) 1b-1430.70-0.95 (m, 26 H), 1.20-1.88 (m, 16 H), 2.68-3.02 (m, 16 H), 4.40-4.50(m, 1 H), 4.51 (bs, 4 H), 4.98-5.69 (m, 13 H), 7.10-7.35 (m, 10 H)1b-144 0.70-0.95 (m, 26 H), 1.20-1.88 (m, 16 H), 2.68-3.02 (m, 16 H),4.40-4.50 (m, 1 H), 4.51 (bs, 4 H), 4.98-5.69 (m, 13 H), 7.10-7.35 (m,10 H) 1b-145 0.70-0.95 (m, 26 H), 1.20-1.88 (m, 16 H), 2.68-3.02 (m, 16H), 4.40-4.50 (m, 1 H), 4.51 (bs, 4 H), 4.98-5.69 (m, 13 H), 7.10-7.35(m, 10 H) 1b-146 0.19-0.34 (m, 4 H), 0.46-0.61 (m, 4 H), 0.69-0.97 (m,24 H), 1.11-1.32 (m, 8 H), 1.35-1.40 (m, 1 H), 1.42-1.64 (m, 5 H),1.66-1.76 (m, 1 H), 2.69 (s, 2 H), 2.77 (d, 4 H), 2.83-2.96 (m, 6 H),3.01-3.22 (m, 3 H), 3.37 (br s, 8 H), 3.64 (d, 4 H), 4.98- 5.17 (m, 6H), 5.23 (br dd, 1 H), 5.32-5.56 (m, 2 H), 5.64-5.75 (m, 1 H), 7.12-7.31 (m, 10 H), 7.46-7.51 (m, 2 H) 1b-148 0.65-0.94 (m, 26 H), 1.23-1.90(m, 30 H), 2.67-3.02 (m, 18 H), 4.35-4.45 (m, 1 H), 5.01-5.70 (m, 13 H),6.05 (s, 2 H), 7.11-7.60 (m, 10 H) 1b-149 0.64-0.94 (m, 26 H), 1.18-1.76(m, 16 H), 2.67-3.06 (m, 16 H), 3.77 (s, 6 H), 4.39- 5.72 (m, 12 H),6.38 (s, 2 H), 6.88-6.98 (m, 8 H), 7.20-7.33 (m, 8 H), 7.54 (s, 2 H)1b-151 0.68-0.94 (m, 27 H), 1.23-1.70 (m, 27 H), 2.67-3.01 (m, 16 H),4.42-4.43 (m, 3 H), 5.02-5.67 (m, 11 H), 7.04 (m, 4 H), 7.25-7.35 (m, 8H) 1b-152 0.68-0.94 (m, 26 H), 1.18-1.77 (m, 16 H), 1.91 (s, 6 H), 2.04(s 6 H), 2.67-3.06 (m, 16 H), 4.39-5.71 (m, 12 H), 7.00 (d, 4 H),7.21-7.27 (m, 6 H) 1b-153 0.63-0.93 (m, 26 H), 1.17-1.76 (m, 16 H),2.67-3.05 (m, 16 H), 4.38-5.69 (m, 12 H), 6.49 (s, 2 H), 6.88 (d, 4H),7.19-7.24 (m, 4H), 7.42 (d, 4H), 7.49 (d, 4 H), 7.59 (s, 2 H) 1b-1540.67-0.95 (m, 26 H), 1.19-1.74 (m, 28 H), 1.81-1.91 (m, 4 H), 2.67-3.06(m, 18 H), 4.39-5.69 (m, 12 H), 6.10 (s, 2 H), 7.00 (d, 4 H), 7.23-7.28(m, 4 H), 7.37 (s, 2H) 1b-155 0.67-0.95 (m, 26 H), 1.17-1.74 (m, 16 H),2.67-3.07 (m, 16 H), 3.19 (s, 6 H), 4.24 (s, 4 H), 4.39-5.70 (m, 12H),7.12-7.18 (m, 4H), 7.25-7.30 (m, 4H), 7.40 (s, 2H), 7.73 (s, 2H) 1b-1560.65-0.94 (m, 26 H), 1.20-1.75 (m, 16 H), 2.67-3.04 (m, 16 H), 4.35-4.45(m, 1 H), 5.00-5.72 (m, 11 H), 5.98 (s, 2 H), 6.99-7.78 (m, 12 H) 1b-1570.67-0.94 (m, 26 H), 1.09 (t, 6 H), 1.18-1.76 (m, 16 H), 2.67-3.08 (m,16 H), 3.40 (q, 4 H), 4.28 (s, 4 H), 4.39-5.72 (m, 12 H), 7.15 (d, 4 H),7.27 (d, 4 H), 7.39 (s, 2 H), 7.71-7.73 (m, 2 H) 1b-158 0.68-0.95 (m, 26H), 1.18-1.76 (m, 16 H), 2.09 (s, 6 H), 2.68-3.07 (m, 16 H), 4.26 (s, 4H), 4.39-5.72 (m, 12 H), 7.15 (d, 4 H), 7.27 (d, 4 H), 7.52-7.54 (m, 2H) 1b-159 0.65-0.95 (m, 26 H), 1.17-1.76 (m, 22 H), 2.05 (s, 6 H),2.68-3.07 (m, 16 H), 4.07 (q, 4 H), 4.39-5.72 (m, 14 H), 7.05 (d, 4 H),7.24-7.27 (m, 4 H) 1b-160 0.68-0.94 (m, 26 H), 1.18-1.74 (m, 16 H), 2.16(s, 6 H), 2.67-3.07 (m, 16 H), 4.39- 5.70 (m, 12 H), 6.06 (s, 2 H), 7.01(d, 4 H), 7.26 (d, 4 H), 7.34 (s, 2 H) 1b-161 0.67-0.94 (m, 26 H),1.33-2.40 (m, 28 H), 2.78-3.02 (m, 16 H), 4.40-4.50 (m, 1 H), 4.62-4.72(m, 2H), 5.0-5.60 (m, 13 H), 7.12 (d, J = 7.7 Hz, 4 H), 7.26 (d, J = 7.9Hz, 4 H), 7.53-7.55 (m, 2 H) 1b-162 0.68-0.94 (m, 26 H), 1.18-1.76 (m,16 H), 2.67-3.08 (m, 16 H), 4.39-5.73 (m, 16 H), 7.24 (d, 4 H), 7.31 (d,4 H), 7.91 (s, 2 H) 1b-163 0.68-0.95 (m, 26 H), 1.16-1.75 (m, 22 H),2.05 (s, 6 H), 2.68-3.06 (m, 16 H), 4.07 (q, 4 H), 4.39-5.72 (m, 14 H),7.05 (d, 4 H), 7.24-7.27 (m, 4 H) 1b-164 0.67-0.96 (m, 26 H), 1.18-1.76(m, 28 H), 2.05 (s, 6 H), 2.67-3.06 (m, 16 H), 4.37- 5.71 (m, 16 H),7.05 (d, 4 H), 7.23-7.27 (m, 4 H) 1b-165 0.68-0.94 (m, 26 H), 1.09 (t, 6H), 1.18-1.76 (m, 16 H), 2.48-2.54 (m, 4 H), 2.67-3.07 (m, 16H),4.39-5.70 (m, 12 H), 6.09 (s, 2 H), 7.00 (d, 4 H), 7.26 (d, 4 H), 7.37(s, 2 H) 1b-166 0.68-0.95 (m, 26 H), 1.18-1.76 (m, 16 H), 2.67-3.06 (m,16 H), 3.20 (s, 6 H), 4.39- 5.71 (m, 16 H), 6.28 (s, 2 H), 7.06 (d, 4H), 7.26 (d, 4 H), 7.42 (s, 2 H) 1b-167 0.49-1.10 (m, 26H), 1.10-1.77(m, 26H), 1.83-2.11 (m, 1H), 2.63-3.10 (m, 10H), 3.13-3.27 (m, 2H),3.33-3.47 (m, 1H), 4.05-4.20 (m, 2H), 4.32-4.61 (m, 2H), 4.77- 5.76 (m,11H), 6.97-7.36 (m, 8H), 7.37-7.78 (m, 4H) 1b-168 0.67-0.95 (m, 26 H),1.18-1.74 (m, 16 H), 2.06 (s, 6 H), 2.68-3.07 (m, 16 H), 3.80 (s, 6 H),4.39-5.72 (m, 14 H), 7.04 (d, 4 H), 7.23-7.27 (m, 4 H) 1b-169 0.67-0.95(m, 26 H), 1.09-1.75 (m, 28 H), 2.42 (q, 4 H), 2.68-3.09 (m, 16 H), 4.07(q, 4 H), 4.39-5.72 (m, 14 H), 7.05 (d, 4 H), 7.25 (d, 4 H) 1b-1700.55-0.95 (m, 34 H), 1.17-1.76 (m, 24 H), 2.68-3.07 (m, 16 H), 4.05 (q,4 H), 4.39- 5.72 (m, 14 H), 7.03 (d, 4 H), 7.24-7.27 (m, 4 H) 1b-1710.65-1.05 (m, 26 H) 1.18-1.76 (m, 22 H) 1.84 (br s, 12 H) 2.63-3.10 (m,16 H) 3.82-3.96 (m, 3 H) 4.37-4.48 (m, 1 H) 4.97-5.76 (m, 11 H) 6.86 (m,4 H) 7.15- 7.32 (m, 6 H) 7.45-7.59 (m, 2 H) 1b-172 0.67-0.94 (m, 35 H),1.21-1.94 (m, 21 H), 2.67-3.29 (m, 16 H), 3.55-3.57 (m, 4 H), 4.40-4.50(m, 1 H), 5.07-5.69 (m, 11 H), 7.13 (d, J = 7.8 Hz, 4 H), 7.19 (s, 2 H),7.27 (d, J = 7.5 Hz, 4 H), 7.47-7.48 (m, 2 H) 1b-173 0.63-0.92 (m, 26H), 1.13-1.71 (m, 16 H), 2.66-3.02 (m, 16 H), 4.36-5.67 (m, 8 H), 5.91(s, 4 H), 6.86-6.88 (m, 2 H), 6.98 (d, 4 H), 7.15-7.19 (m, 4 H),7.33-7.37 (m, 2 H), 7.57 (s, 2 H), 7.77 (d, 2 H), 7.84-7.89 (m, 2 H),8.62 (d, 2 H) 1b-174 0.68-0.93 (m, 28 H), 1.23-1.83 (m, 14 H), 2.65-3.18(m, 16 H), 4.40-4.50 (m, 1 H), 5.01-5.72 (m, 11 H), 7.17-7.19 (m, 6 H),7.25-7.27 (m, 2 H), 7.28-7.31 (m, 4 H), 7.63 (s, 2 H), 8.10-8.13 (m, 2H)1b-175 0.66-0.94 (m, 26 H), 1.20-1.80 (m, 16 H), 2.66-3.31 (m, 16 H),4.40-4.50 (m, 1 H), 5.01-5.69 (m, 11 H), 6.98 (d, J = 8.3 Hz, 2H), 7.10(t, J = 6.1 Hz, 2H), 7.20 (d, J = 7.7 Hz, 4 H), 7.29 (d, J = 7.8 Hz, 4H), 7.47 (s, 2 H), 7.81 (t, J = 7.2 Hz, 2 H), 7.93 (d, J = 5.2 Hz, 2 H),8.15 (s, 2 H) 1b-176 0.67-0.95 (m, 26 H), 1.06 (t, 6 H), 1.18-1.76 (m,16 H), 2.67-3.07 (m, 16 H), 3.40 (q, 4 H), 4.39-5.70 (m, 16 H), 6.27 (s,2 H), 7.07 (d, 4 H), 7.25 (d, 4 H), 7.40 (s, 2 H) 1b-177 0.63-0.92 (m,26 H), 1.13-1.70 (m, 16 H), 2.50 (s, 6 H), 2.66-3.02 (m, 16 H), 4.36-5.67 (m, 8 H), 5.91 (s, 4 H), 6.83 (s, 2 H), 7.03 (d, 4 H), 7.17-7.21(m, 6 H), 7.54- 7.58 (m, 4 H), 7.72-7.77 (m, 2 H) 1b-178 0.66-0.96 (m,26 H), 1.14-1.76 (m, 22 H), 2.65-3.06 (m, 16 H), 4.19 (q, 4 H), 4.38-5.72 (m, 12 H), 6.21-6.23 (m, 2 H), 7.11-7.15 (m, 4 H), 7.26-7.29 (m, 6H), 7.34-7.38 (m, 4 H), 7.73 (d, 4 H) 1b-179 0.67-0.94 (m, 27 H),1.21-1.87 (m, 15 H), 2.32-3.06 (m, 24 H), 3.65-3.68 (m, 8 H), 4.40-4.50(m, 1 H), 5.01-5.71 (m, 11 H), 7.12 (d, J = 7.8 Hz, 4 H), 7.19 (s, 2 H),7.26 (d, J = 7.7 Hz, 4 H), 7.31-7.32 (m, 2 H) 1b-180 0.66-0.94 (m, 26H), 1.21-1.80 (m, 34 H), 2.67-3.21 (m, 16 H), 3.17-3.32 (m, 4 H), 3.76(t, J = 5.5 Hz, 4 H), 4.40-4.50 (m, 1 H), 5.01-5.69 (m, 11 H), 6.93-6.96(m, 2 H), 7.10-7.27 (m, 10 H), 7.49 (s, 2 H) 1b-181 0.49-0.53 (m, 4 H),0.68-0.95 (m, 30 H), 1.20-1.78 (m, 18 H), 2.07 (s, 6 H), 2.67- 3.06 (m,16 H), 4.39-5.70 (m, 14 H), 7.06 (d, 4 H), 7.26 (d, 4 H) 1b-1820.67-0.94 (m, 29 H), 1.21-1.83 (m, 21 H), 2.53-3.02 (m, 24 H), 4.40-4.50(m, 1 H), 5.07-5.69 (m, 11 H), 7.00 (s, 2 H), 7.10-7.13 (m, 6 H),7.24-7.26 (m, 4 H) 1b-183 0.70-0.94 (m, 28 H), 1.06-1.87 (m, 26 H),2.67-3.02 (m, 24 H), 4.35-4.45 (m, 1 H), 5.13-5.69 (m, 11 H), 7.10-7.15(m, 6 H), 7.24-7.27 (m, 6 H) 1b-184 0.70-0.94 (m, 25 H), 1.06-1.08 (m,12 H), 1.21-1.87 (m, 17 H), 2.67-3.02 (m, 16 H), 3.56-3.60 (m, 2 H),4.28 (s, 4 H), 4.40-4.50 (m, 1 H), 5.01-5.69 (m, 11 H), 7.14-7.16 (m, 4H), 7.26-7.28 (m, 4 H), 7.37 (s, 2 H), 7.68 (s, 2 H) 1b-185 0.87-0.94(m, 27 H), 1.23-1.70 (m, 15 H), 2.68-2.13 (m, 20 H), 3.78 (bs, 4 H),4.40-4.51 (m, 1 H), 5.08-5.71 (m, 11 H), 7.13 (d, J = 7.5 Hz, 4 H),7.21-7.30 (m, 6 H), 7.60 (bs, 2 H), 8.04 (bs, 6 H) 1b-186 0.69-0.95 (m,26 H), 1.05-1.14 (m, 6 H), 1.20-1.74 (m, 16 H), 2.11 (s, 6 H), 2.43-2.51 (m, 4 H), 2.67-3.06 (m, 16 H), 4.39-5.70 (m, 12 H), 5.87-5.89 (m, 2H), 7.00 (d, 4 H), 7.25-7.28 (m, 4 H) 1b-187 0.69-0.95 (m, 26 H), 1.07(t, 6 H), 1.20-1.74 (m, 16 H), 2.11 (s, 6 H), 2.43-2.52 (m, 4 H),2.67-3.06 (m, 16 H), 4.39-5.70 (m, 12 H), 5.88 (s, 2 H), 7.00 (d, 4 H),7.24-7.28 (m, 4 H) 1b-188 0.88-0.94 (m, 26 H), 1.16-1.53 (m, 28 H),2.00-2.03 (m, 12 H), 2.68-3.01 (m, 16 H), 3.86-3.90 (m, 2 H), 4.40-4.50(m, 1 H), 5.01-5.68 (m, 11 H), 6.97 (d, J = 7.7 Hz, 4 H), 7.25 (d, J =7.8 Hz, 4 H) 1b-189 0.63-0.92 (m, 26 H), 1.14-1.71 (m, 16 H), 2.66-3.02(m, 16 H), 4.36-5.67 (m, 8 H), 5.84 (s, 4 H), 6.86-6.88 (m, 2 H), 6.98(d, 4 H), 7.16-7.19 (m, 4 H), 7.57 (s, 2 H), 7.79-7.89 (m, 4 H),8.62-8.64 (m, 2 H) 1b-190 0.64-0.94 (m, 26 H), 1.16-1.72 (m, 16 H),2.67-3.04 (m, 16 H), 3.86 (s, 6 H), 4.37- 5.68 (m, 12 H), 6.48 (s, 2 H),6.86-6.90 (m, 6 H), 7.20-7.25 (m, 4 H), 7.59 (s, 2 H), 7.70-7.75 (m, 2H), 8.13-8.15 (m, 2 H) 1b-191 0.70-0.94 (m, 28 H), 1.15-1.87 (m, 20 H),2.02-2.05 (m, 12 H), 2.67-3.31 (m, 16 H), 3.76-3.81 (m, 4 H), 4.40-4.50(m, 1 H), 5.01-5.71 (m, 11 H), 6.98-7.00 (m, 4 H), 7.24-7.26 (m, 4 H)1b-192 0.55-0.94 (m, 27 H), 1.14-1.87 (m, 15 H), 2.57-3.11 (m, 16 H),3.35-3.55 (m, 12 H), 4.40-4.50 (m, 1 H), 4.83-5.71 (m, 11 H), 7.09-7.11(m, 4 H), 7.34-7.36 (m, 4 H), 7.99-8.00 (m, 4 H) 1b-193 0.92-0.98 (m, 37H), 1.23-1.70 (m, 17 H), 2.50-3.32 (m, 24 H), 4.40-4.51 (m, 1 H),5.10-5.69 (m, 11 H), 7.07-7.11 (m, 6 H), 7.18-7.27 (m, 6 H) 1b-1950.71-0.91 (m, 25 H), 1.23-1.74 (m, 17 H), 2.64-3.03 (m, 16 H), 4.40-4.45(m, 1 H), 5.01-5.70 (m, 11 H), 6.90 (bs, 2 H), 7.24-7.31 (m, 8 H),7.96-7.97 (m, 2 H), 8.52-8.53 (m, 2 H), 8.61 (bs, 2 H), 9.09 (s, 2 H)1b-196 0.86-0.95 (m, 25 H), 1.29-1.74 (m, 17 H), 2.67-3.03 (m, 16 H),4.40-4.45 (m, 1 H), 5.01-5.70 (m, 11 H), 6.59 (s, 2 H), 7.22-7.24 (m, 4H), 7.30-7.38 (m, 8 H), 7.93 (s, 2 H) 1b-197 0.87-0.94 (m, 25 H),1.21-1.28 (m, 12 H), 1.33-1.70 (m, 10 H), 1.99 (s, 6 H), 2.67-3.02 (m,16 H), 3.85-3.91 (m, 4 H), 4.40-4.43 (m, 1 H), 5.01-5.68 (m, 12 H),6.98-7.00 (m, 4 H), 7.25-7.27 (m, 6 H) 1b-198 0.90-0.94 (m, 25 H),1.14-1.28 (m, 12 H), 1.34-1.70 (m, 10 H), 2.00 (s, 6 H), 2.67-3.03 (m,16 H), 3.78-3.83 (m, 4 H), 4.40-4.42 (m, 1 H), 5.01-5.71 (m, 12 H),7.11-7.13 (m, 4 H), 7.25-7.27 (m, 4 H), 7.39-7.42 (m, 2 H) 1b-1990.67-0.94 (m, 26 H), 1.11-1.82 (m, 27 H), 2.13 (s, 6 H), 2.67-3.03 (m,16 H), 3.98-4.04 (m, 2 H), 4.40-4.42 (m, 1 H), 5.03-5.69 (m, 12 H),7.11-7.12 (m, 4 H) 7.26-7.27 (m, 4 H), 7.43-7.44 (m, 2 H) 1b-2010.67-0.94 (m, 26 H), 1.23-1.81 (m, 16 H), 2.67-3.03 (m, 16 H), 3.34 (s,6 H), 4.39-4.42 (m, 1 H), 4.90 (s, 4 H), 5.01-5.72 (m, 11 H), 7.14-7.53(m, 12 H) 1b-202 0.67-0.96 (m, 26 H), 1.23-1.70 (m, 16 H), 2.68-3.07 (m,16 H), 4.15-4.19 (m, 4 H), 4.35-4.45 (m, 1 H), 4.86 (s, 4 H), 5.01-5.74(m, 11 H), 6.98-7.49 (m, 12 H, 12.21-12.34 (m, 2 H) 1b-203 0.68-0.94 (m,26 H), 1.20-1.69 (m, 16 H), 2.67-3.03 (m, 16 H), 3.26 (6H, s), 3.55-3.57 (m, 4 H), 3.90-3.92 (m, 4 H), 4.35-4.45 (m, 1 H), 5.01-5.70 (m, 11H), 7.12- 7.50 (m, 12 H) 1b-205 0.69-0.98 (m, 32 H), 1.18-1.76 (m, 20H), 2.45-2.51 (m, 4 H), 2.67-3.07 (m, 16 H), 4.39-5.70 (m, 12 H), 6.09(s, 2 H), 7.00 (d, 4 H), 7.24-7.28 (m, 4 H), 7.38 (s, 2 H) 1b-2060.07-0.10 (m, 4 H), 0.42-0.47 (m, 4 H), 0.68-0.95 (m, 28 H), 1.19-1.75(m, 16 H), 2.41-2.45 (m, 4 H), 2.67-3.06 (m, 16 H), 4.39-5.70 (m, 12 H),6.20 (s, 2 H), 6.99 (d, 4 H), 7.24-7.28 (m, 4 H), 7.38 (s, 2 H) 1b-2070.65-0.95 (m, 26 H), 1.18-1.75 (m, 16 H), 2.63-3.06 (m, 22 H), 4.38-5.67(m, 12 H), 6.67 (s, 2 H), 6.90 (d, 4 H), 7.22-7.26 (m, 4 H), 7.67 (s, 2H), 8.67-8.70 (m, 4 H) 1b-208 0.63-0.91 (m, 26 H), 1.14-1.70 (m, 16 H),2.66-3.03 (m, 16 H), 4.36-5.67 (m, 8 H), 5.86 (s, 4 H), 7.00 (d, 4 H),7.10 (s, 2 H), 7.17-7.21 (m, 4 H), 7.65 (s, 2 H), 8.58 (s, 2 H), 8.67(s, 2 H), 9.08 (s, 2 H) 1b-209 0.69-0.95 (m, 38 H), 1.20-1.80 (m, 18 H),2.41 (d, 4 H), 2.67-3.06 (m, 16 H), 4.39- 5.69 (m, 12 H), 6.08 (s, 2 H),7.00 (d, 4 H), 7.24-7.28 (m, 4 H), 7.39 (s, 2 H) 1b-210 0.68-1.03 (m, 38H), 1.22-1.76 (m, 20 H), 2.66-3.06 (m, 18 H), 4.38-5.69 (m, 12 H), 6.09(s, 2 H), 7.01 (d, 4 H), 7.24-7.28 (m, 4 H), 7.39 (s, 2 H) 1b-2110.68-0.96 (m, 26 H), 1.21-1.76 (m, 16 H), 2.67-3.06 (m, 16 H), 4.39-5.70(m, 12 H), 6.85 (s, 2 H), 7.08 (d, 4 H), 7.17-7.44 (m, 6 H), 7.59 (s, 2H) 1b-212 0.70-0.97 (m, 26 H), 1.20-1.75 (m, 22 H), 2.67-3.06 (m, 22 H),4.39-5.69 (m, 14 H), 6.24 (s, 2 H), 7.05 (d, 4 H), 7.26 (d, 4 H), 7.43(s, 2 H) 1b-213 0.68-0.96 (m, 26 H), 1.20-1.76 (m, 26 H), 1.87-1.95 (m,4 H), 2.66-3.05 (m, 16 H), 3.37-3.55 (m, 8 H), 4.39-5.66 (m, 12 H), 6.16(s, 2 H), 6.90 (d, 4 H), 7.24 (d, 4 H) 7.45 (s, 2 H) 1b-214 0.67-1.09(m, 38 H), 1.18-1.75 (m, 16 H), 2.64-3.09 (m, 26 H), 4.39-5.69 (m, 12 H)6.13 (s, 2 H), 6.98 (d, 4 H), 7.24 (d, 4 H), 7.38 (s, 2 H) 1b-2150.68-1.00 (m, 30 H), 1.17-1.75 (m, 20 H), 2.67-3.07 (m, 16 H), 4.38-5.70(m, 12 H), 6.43 (s, 2 H), 7.08 (d, 4 H), 7.26 (d, 4 H), 7.48 (s, 2 H)1b-216 0.69-0.98 (m, 26 H), 1.20-1.82 (m, 18 H), 1.98-2.09 (m, 2 H),2.67-3.06 (m, 18 H), 4.39-5.70 (m, 12 H), 6.18 (s, 2 H), 7.05-7.10 (m, 4H), 7.27 (d, 4 H), 7.42 (s, 2 H) 1b-217 0.68-1.01 (m, 26 H), 1.15-1.75(m, 24 H), 2.66-3.08 (m, 16 H), 4.38-5.71 (m, 12 H) 6.37 (s, 2 H), 7.09(d, 4 H), 7.25-7.30 (m, 4 H), 7.43 (s, 2H) 1b-218 0.67-0.95 (m, 32 H),1.00 (br s, 1 H), 1.07 (br s, 1 H), 1.17-1.32 (m, 9 H), 1.33- 1.48 (m, 4H), 1.48-1.75 (m, 5 H), 2.67 (s, 2 H), 2.75 (br d, 4 H), 2.82-2.94 (m, 6H), 3.03 (br d, 3 H), 4.41 (br d, 1 H), 4.78-5.07 (m, 2 H), 5.07-5.26(m, 4 H), 5.34 (q, 1 H), 5.42-5.55 (m, 5 H), 5.56-5.75 (m, 1 H), 6.19(s, 2 H), 7.04 (br d, 4 H), 7.26 (br d, 4 H), 7.37 (s, 2 H) 1b-2190.65-0.90 (m, 32 H), 0.94 (br d, 2 H), 1.14 (s, 5 H), 1.22-1.31 (m, 5H), 1.32-1.39 (m, 2 H), 1.40-1.57 (m, 4 H), 1.57-1.78 (m, 3 H), 2.67 (s,2 H), 2.75 (d, 4 H), 2.81- 2.94 (m, 6 H), 2.97-3.10 (m, 3 H), 3.33 (s, 8H), 5.03 (q, 1 H), 5.08-5.26 (m, 3 H), 5.31-5.51 (m, 5 H), 5.56-5.71 (m,1 H), 6.08 (s, 2 H), 7.02 (br d, 3 H), 7.27 (br dd, 3 H), 7.36 (s, 2 H)1b-220 0.69-0.96 (m, 32 H), 1.21-1.74 (m, 9 H), 1.47-1.74 (m, 6 H),2.65-2.85 (m, 9 H), 2.85-2.92 (m, 11 H), 3.03 (br d, 3 H), 3.35 (s, 10H), 4.41 (br d, 1 H), 5.03 (q, 1 H), 5.12 (br d, 3 H), 5.18-5.38 (m, 2H), 5.41-5.55 (m, 5 H), 5.58-5.73 (m, 1 H) 6.23 (s, 2 H), 7.02 (br d, 4H), 7.26 (br dd, 4 H), 7.44 (s, 2 H) 1b-221 0.69-0.95 (m, 32 H),0.98-1.75 (m, 8 H), 2.66 (s, 2 H), 2.69-2.79 (m, 4 H), 2.81- 2.93 (m, 6H), 2.96-3.10 (m, 3 H), 3.32 (s, 8 H), 4.38-4.50 (m, 4 H), 4.63-4.71 (m,4 H), 4.92-5.07 (m, 1 H), 5.08-5.15 (m, 7 H), 5.17-5.36 (m, 2 H),5.39-5.52 (m, 2 H), 5.57-5.71 (m, 1 H), 6.14 (s, 2 H), 7.00 (m, 4 H),7.27 (m, 4H), 7.45 (s.2 H) 1b-222 0.55-1.01 (m, 38 H), 1.08 (br d, 1 H),1.20-1.31 (m, 6 H), 1.35-1.62 (m, 8 H), 1.65-1.73 (m, 2 H), 2.67 (s, 2H), 2.76 (br d, 4 H), 2.82-2.94 (m, 6 H), 3.02 (br s, 3 H), 3.31 (s, 4H), 4.38-4.45 (m, 1 H), 4.96-5.17 (m, 3 H), 5.19-5.26 (m, 1 H),5.29-5.51 (m, 6 H), 5.60-5.71 (m, 1 H), 5.86 (s, 2 H), 6.99-7.13 (m, 4H), 7.21- 7.35 (m, 4 H) 1b-223 0.67-0.94 (m, 26H), 1.26-2.11 (m, 24H),2.67-3.01 (m, 16H), 3.70-3.82 (m, 4H), 4.35-4.45 (m, 1H), 4.86-4.88 (m,2H), 5.08-5.67 (m, 11H), 6.24 (s, 2H), 7.03-7.25 (m, 8H), 7.39 (s, 2H)1b-224 0.67-0.94 (m, 26H), 1.26-1.71 (m, 16H), 2.67-3.02 (m, 24H),3.38-3.40 (m, 2H), 4.35-4.45 (m, 1H), 5.10-5.63 (m, 11H), 6.32 (s, 2H),7.00-7.27 (m, 8H), 7.42 (s, 2H) 1b-225 0.67-0.94 (m, 26H), 1.26-1.77 (m,20H), 2.22-2.26 (m, 8H), 2.65-3.02 (m, 22H), 4.40-4.43 (m, 1H),5.10-5.67 (m, 11H), 6.41 (s, 2H), 7.04-7.25 (m, 8H), 7.46 (s, 2H) 1b-2260.67-0.94 (m, 26H), 1.26-1.77 (m, 16H), 2.65-3.02 (m, 16H), 4.40-4.43(m, 1H), 5.08-5.67 (m, 15H), 6.41 (s, 2H), 6.90-7.28 (m, 18H), 7.46 (s,2H) 1b-227 0.67-0.94 (m, 26H), 1.26-1.77 (m, 16H), 2.65-3.08 (m, 24H),4.40-4.43 (m, 1H), 4.55-4.60 (m, 2H), 5.08-5.67 (m, 11H), 6.45 (s, 2H),6.98-7.27 (m, 8H), 7.43 (s, 2H) 1b-228 0.67-1.06 (m, 38H), 1.26-1.77 (m,16H), 2.65-3.02 (m, 16H), 3.55-3.58 (m, 2H), 4.41 (s, 5H), 5.08-5.67 (m,11H), 6.26 (s, 2H), 7.05-7.07 (m, 4H), 7.24-7.27 (m, 4H), 7.39 (s, 2H)1b-229 0.67-0.94 (m, 26H), 1.26-2.05 (m, 32H), 2.65-3.02 (m, 22H),4.40-4.42 (m, 1H), 5.08-5.67 (m, 11H), 6.28 (s, 2H), 7.00-7.02 (m, 4H),7.23-7.25 (m, 4H), 7.43 (s, 2H) 1b-230 0.67-0.94 (m, 26H), 1.07 (s,12H), 1.26-1.73 (m, 16H), 2.65-3.02 (m, 20H), 4.40- 4.42 (m, 1H), 4.52(s, 2H), 5.08-5.67 (m, 11H), 6.12 (s, 2H), 6.97-6.99 (m, 4H), 7.25-7.27(m, 4H), 7.37 (s, 2H) 1b-231 0.69-1.00 (m, 26 H), 1.20-1.81 (m, 18 H),2.06-2.16 (m, 2 H), 2.66-3.07 (m, 16 H), 3.31-3.49 (m, 6 H), 3.67-3.84(m, 4 H), 4.39-5.69 (m, 12 H), 6.18 (s, 2 H), 7.02 (d, 4 H), 7.25-7.29(m, 4 H), 7.41 (s, 2 H) 1b-232 0.64-0.93 (m, 26 H), 1.14-1.73 (m, 16 H),2.66-3.04 (m, 16 H), 4.36-5.68 (m, 8 H), 5.86 (s, 4 H), 6.89 (s, 2 H),7.03 (d, 4 H), 7.19-7.23 (m, 4 H), 7.60 (s, 2 H), 7.85 (d, 2 H), 7.93(d, 2 H) 1b-233 0.66-0.94 (m, 26 H), 1.18-1.70 (m, 16 H), 2.29 (s, 6 H),2.66-3.04 (m, 16 H), 4.37- 5.68 (m, 12 H), 6.16 (s, 2 H), 6.48-6.54 (m,4 H), 7.00 (d, 4 H), 7.23-7.27 (m, 4 H), 7.53 (s, 2H) 1b-234 0.54-1.78(m, 62 H), 2.66-3.32 (m, 16 H), 5.07-5.94 (m, 12 H), 7.07 (m, 4 H),7.23-7.32 (m, 5 H), 7.35 (s, 1 H) 1b-235 0.58-0.95 (m, 28 H), 1.12-1.70(m, 24 H), 2.24 (br d, 2 H), 2.44-2.49 (m, 1 H), 2.65-2.70 (m, 1 H),2.77-3.04 (m, 14 H), 3.31 (s, 6 H), 4.17 (s, 1 H), 5.01-5.67 (m, 9 H),6.17 (s, 2 H), 7.10 (br d, 4 H), 7.30 (br d, 4 H), 7.41 (s, 2 H)

The following Formula (1A1-3) compounds described in Table 1c wereprepared in accordance with the schemes and examples described herein.

The following Formula (1A1-3) compounds described in Table 1c wereprepared in accordance with the schemes and examples described herein.Examples 1c-1, 1c-2, and 1c-3 are examples wherein R^(c) and R^(d) areeach alkyl and wherein the alkyls join together to form a cycloalkylring (e.g., cyclobutyl); and wherein R^(c′) and R^(d′) are each alkyland wherein the alkyls join together to form a cycloalkyl ring (e.g.,cyclobutyl).

TABLE 1c Compounds of Formula (1A1-3). # 3 and 3′ 4 and 4′ 5 and 5′R^(c) and R^(d) R^(c)′ and R^(d)′ 1c-1 H H H

1c-2 H Cl H

1c-3 H isopropoxy H

# 3 and 3′ 4 and 4′ 5 and 5′ R^(c) and R^(c)′ R^(d) and R^(d)′ 1c-4 H HH H

1c-5 H isopropoxy H H

1c-6 H H H methyl methyl 1c-7 H —NO₂ H methyl methyl 1c-8 H

H methyl methyl 1c-9 H methyl H methyl methyl  1c-10 H isopropoxy Hmethyl methyl  1c-11 H Br H methyl methyl  1c-12 —NO₂ H H methyl methyl 1c-13 —CF₃ H —CF₃ H methyl

The following Formula (1A1-3) compounds and example #'s refer to thosecompounds depicted in Table 1c. In one aspect of the invention, areFormula (1A1-3) compounds selected from the group consisting of:

-   (1c-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(1-(1H-pyrazol-1-yl)cyclobutyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1190);-   (1c-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(1-(4-chloro-1H-pyrazol-1-yl)cyclobutyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1258);-   (1c-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(1-(4-isopropoxy-1H-pyrazol-1-yl)cyclobutyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1306);-   (1c-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(cyclopropyl(1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1190);-   (1c-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(cyclopropyl(4-isopropoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1306);-   (1c-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(2-(1H-pyrazol-1-yl)propan-2-yl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (1c-7).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(2-(4-nitro-1H-pyrazol-1-yl)propan-2-yl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1255);-   (1c-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(2-(4-cyclopropyl-1H-pyrazol-1-yl)propan-2-yl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1246);-   (1c-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(2-(4-methyl-1H-pyrazol-1-yl)propan-2-yl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (1c-10).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(2-(4-isopropoxy-1H-pyrazol-1-yl)propan-2-yl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1282);-   (1c-11).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(2-(4-bromo-1H-pyrazol-1-yl)propan-2-yl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1323);-   (1c-12).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(2-(3-nitro-1H-pyrazol-1-yl)propan-2-yl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1255); and-   (1c-13).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((R)-1-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)benzyl)-18-(4-((S)-1-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1409).

TABLE 1c′ Formula (1A1-3) Compound NMRs (1H NMR (400 Mhz, DMSO-d₆) δppm) Example NMR  1c-1 0.65-1.06 (m, 26 H) 1.15-2.03 (m, 20 H) 2.62-3.11(m, 24 H) 4.37-4.46 (m, 1 H) 4.99-5.75 (m, 7 H) 6.21-6.30 (m, 2 H)7.09-7.20 (m, 4 H) 7.23-7.34 (m, 4 H) 7.44-7.52 (m, 2 H) 7.64-7.75 (m, 2H) 1c-3 0.61-1.07 (m, 26H), 1.12-1.77 (m, 27H), 1.78-2.05 (m, 4H),2.59-3.17 (m, 23H), 4.08-4.23 (m, 2H), 4.35-4.51 (m, 1H), 4.99-5.77 (m,10H), 7.03-7.18 (m, 4H), 7.18-7.33 (m, 6H), 7.35-7.54 (m, 2H) 1c-40.29-0.52 (m, 4 H) 0.52-0.98 (m, 28 H) 1.14-1.82 (m, 20H) 2.63-3.12 (m,16 H) 4.35-4.50 (m, 1 H) 4.63-4.72 (m, 2 H) 4.98-5.76 (m, 7 H) 6.22-6.29(m, 2 H) 7.18-7.32 (m, 8 H) 7.39-7.46 (m, 2 H) 7.85-7.94 (m, 2 H) 1c-50.28-1.80 (m, 64 H) 2.63-2.98 (m, 16 H) 4.07-4.20 (m, 2 H) 4.36-4.46 (m,1 H) 4.46-4.55 (m, 2 H) 4.99-5.74 (m, 7 H) 7.15 (s, 2 H) 7.17-7.30 (m, 8H) 7.56-7.63 (m, 2 H) 1c-6 0.60-1.07 (m, 26 H) 1.16-1.77 (m, 16 H)1.82-1.96 (m, 12 H) 2.63-3.09 (m, 16 H) 4.36-4.46 (m, 1 H) 4.97-5.72 (m,7 H) 6.26-6.36 (m, 2 H) 6.79-6.90 (m, 4 H) 7.20 (br d, J = 7.82 Hz, 4 H)7.45-7.53 (m, 2 H) 7.76-7.86 (m, 2 H) 1c-7 0.61-1.10 (m, 26 H) 1.12-1.75(m, 16 H) 1.95 (s, 12 H) 2.63-3.10 (m, 16 H) 4.36-4.50 (m, 1 H)4.97-5.74 (m, 7 H) 7.02-7.10 (m, 4 H) 7.22-7.32 (m, 4 H) 8.24-8.34 (m, 2H) 8.92-9.02 (m, 2 H) 1c-9 0.62-1.08 (m, 26 H) 1.17-1.76 (m, 16 H)1.79-1.92 (m, 12 H) 2.02 (s, 6 H) 2.65-3.09 (m, 16 H) 4.38-4.46 (m, 1 H)4.97-5.73 (m, 7 H) 6.83-6.93 (m, 4 H) 7.16-7.25 (m, 4 H) 7.26-7.34 (m, 2H) 7.51-7.58 (m, 2 H)  1c-10 0.66-1.07 (m, 26 H) 1.14-1.77 (m, 28 H)1.80-1.90 (m, 12 H) 2.64-3.07 (m, 16 H) 4.12-4.24 (m, 2 H) 4.38-4.47 (m,1 H) 4.98-5.73 (m, 7 H) 6.81-6.90 (m, 4 H) 7.17-7.26 (m, 6 H) 7.48-7.54(m, 2 H)  1c-11 0.70-0.94 (m, 26 H), 1.23-1.89 (m, 16 H), 2.32-2.42 (m,12 H), 2.45-3.31 (m, 16 H), 4.40-4.50 (m, 1 H), 5.10-5.68 (m, 7 H),6.90-6.93 (m, 4 H), 7.22- 7.24 (m, 4 H), 7.58-7.59 (m, 2 H), 8.06-8.08(m, 2 H)  1c-12 0.62-1.09 (m, 28 H) 1.13-1.77 (m, 17 H) 1.96 (s, 12 H)2.63-2.98 (m, 13 H) 4.35-4.48 (m, 1 H) 4.96-5.79 (m, 7 H) 7.03 (br d, J= 7.58 Hz, 4 H) 7.08-7.17 (m, 2 H) 7.28 (br d, J = 7.83 Hz, 4 H)8.11-8.24 (m, 2 H)  1c-13 0.70-0.90 (m, 25 H), 1.23-1.59 (m, 17H), 1.83(s, 6 H), 2.65-3.18 (m, 16 H), 4.40-4.50 (m, 1 H), 5.02-5.84 (m, 9 H),7.16-7.30 (m, 8 H), 7.59 (s, 2 H)

The following compound (mass; NMR):(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propan-2-yl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone(1224; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69-1.00 (m, 26H) 1.06-1.77 (m,16H) 1.81-1.94 (m, 18H) 2.24-2.32 (m, 6H) 2.65-3.14 (m, 16H) 4.42 (brdd, J=10.88, 2.57 Hz, 1H) 4.99-5.78 (m, 7H) 7.08-7.16 (m, 4H) 7.31-7.41(m, 4H)), was prepared similarly to those compounds of Table 1c, but forthe replacement of the pyrazole moiety with a dimethyltriazole moiety.

The following Formula (1B1-1) compounds (hybrid analogs) described inTable 2 were prepared in accordance with the schemes and examplesdescribed herein.

TABLE 2 Formula (1B1-1) Compounds # 3′ 4′ 5′ 2-1  H H H 2-2  H methyl H2-3  H phenyl H 2-4  H pyridin-4yl H 2-5  H 4-F-phenyl H 2-6  H4-Cl-phenyl H 2-7  methyl H methyl 2-8  H t-butyl H 2-9  H ethyl H 2-10H —CN H 2-11 methyl methyl methyl 2-12 H —C(O)OCH₂CH₃ H 2-13 H —C(O)CH₃H 2-14 H

H 2-15 H

H 2-16 methyl Br H 2-17 methyl Br methyl 2-18 H —CHF₂ H 2-19 H —CH₂OH H2-20 H —CF₃ H 2-21 H

H 2-22 H Br H 2-23 H

H 2-24 H

H 2-25 H Cl H 2-26 H propyl H 2-27 H

H 2-28 H F H 2-29 H —NO₂ H 2-30 H —OH H 2-31 H —NHC(O)CH₃ H 2-32

H

2-33 H 6-methyl-pyridin-3-yl H 2-34 H

H 2-35 H —CH₂CH₂OH H 2-36 H —NHS(O)₂CH₃ H 2-37 H pyridin-3-yl H 2-38 H

H 2-39 H ethoxy H 2-40 methyl

methyl 2-41 H I H 2-42 —CH₂OH H —CH₂OH 2-43 methyl —NHC(O)CH₃ methyl2-44 methyl —OH methyl 2-45 H

H 2-46 H

H 2-47 H pyridin-2-yl H 2-48 H

H 2-49 methyl —S(O)₂NH₂ methyl 2-50 methyl Cl methyl 2-51 H —C≡C H 2-52H —CH₂NHC(O)CH₃ H 2-53 H —C(O)NH₂ H 2-54 isopropyl H isopropyl 2-55 —CF₃H —CF₃ 2-56 phenyl H H 2-57 Br H H 2-58 —CF₃ H H 2-59 H —CH₂NH₂ H 2-60methyl

methyl 2-61 H

H 2-62 —CN H —CN 2-63 H —S(O)₂NH₂ H 2-64 H

H 2-65 —CH₂OH H

2-66 H H

2-67 H H phenyl 2-68 H H t-butyl 2-69 H H isopropyl 2-70 H

H 2-71 H

H 2-72 t-butyl H H 2-73 methyl —NH₂ methyl 2-74

H H 2-75 H

H 2-76 H

H 2-77 H

H 2-78 methyl —CN methyl 2-79 methyl F methyl 2-80

—NO₂

2-81 methyl —CF₃ methyl 2-82 ethyl —NO₂ ethyl 2-83 isopropyl H H 2-84 H

H 2-85

—NH₂

2-86 ethyl —NH₂ ethyl 2-87 —NH₂ H H 2-88

H H

The following Formula (1B1-1) compound names and example #s refer tothose compounds depicted in Table 2. In one aspect of the invention, areFormula (1B1-1) compounds selected from the group consisting of:

-   (2-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-[[4-(pyrazol-1-ylmethyl)phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1030);-   (2-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1043);-   (2-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-[[4-[(4-phenylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1105);-   (2-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(pyridin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1106);-   (2-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[[4-(4-fluorophenyl)pyrazol-1-yl]methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1123);-   (2-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[[4-(4-chlorophenyl)pyrazol-1-yl]methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1139);-   (2-7).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[(3,5-dimethylpyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1057);-   (2-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[(4-tert-butylpyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1085);-   (2-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[(4-ethylpyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1057);-   (2-10).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-4-carbonitrile    (1054);-   (2-11).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((3,4,5-trimethyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1071);-   (2-12). ethyl    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate    (1101);-   (2-13).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-acetyl-1H-pyrazol-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1071);-   (2-14).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1142);-   (2-15).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1140);-   (2-16).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-bromo-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1122);-   (2-17).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1136);-   (2-18).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1079);-   (2-19).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1059)-   (2-20).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1097)-   (2-21).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(piperidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1176);-   (2-22).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-bromo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1108);-   (2-23).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(morpholinosulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1178);-   (2-24).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(pyrrolidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1162);-   (2-25).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-chloro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1064);-   (2-26).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1071);-   (2-27).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-(azetidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1148);-   (2-28).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1047);-   (2-29).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1074);-   (2-30).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-hydroxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1045);-   (2-31).    N-(1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazol-4-yl)acetamide    (1086);-   (2-32).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1109);-   (2-33).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(6-methylpyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1120);-   (2-34).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-N-cyclopropyl-1H-pyrazole-4-carboxamide    (1112);-   (2-35).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-(2-hydroxyethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1073);-   (2-36).    N-(1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazol-4-yl)methanesulfonamide    (1122);-   (2-37).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1106);-   (2-38).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-cyclopentyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1097);-   (2-39).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-(hydroxymethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1103);-   (2-40).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-dimethyl-4-(pyrrolidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1190);-   (2-41).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1155);-   (2-42).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-bis(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1089);-   (2-43).    N-(1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetamide    (1114);-   (2-44).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-hydroxy-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1073);-   (2-45).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1107);-   (2-46).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1107);-   (2-47).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1106);-   (2-48). tert-butyl    ((1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazol-4-yl)methyl)carbamate    (1158);-   (2-49).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide    (1136);-   (2-50).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1092);-   (2-51).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-ethynyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1053);-   (2-52).    N-((1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazol-4-yl)methyl)acetamide    (1100);-   (2-53).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide    (1072);-   (2-54).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-diisopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1113);-   (2-55).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (2-56).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((3-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1105);-   (2-57).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3-bromo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1108);-   (2-58).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1097);-   (2-59).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1058);-   (2-60).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-dimethyl-4-(piperidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1205);-   (2-61).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-(cyclopent-1-en-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1095);-   (2-62).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1079);-   (2-63).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-4-sulfonamide    (1108);-   (2-64).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(phenylethynyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1129);-   (2-65).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((5-cyclopropyl-3-(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1099);-   (2-66).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((5-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1069);-   (2-67).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((5-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1105);-   (2-68).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((5-(tert-butyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1085);-   (2-69).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-18-(4-((5-isopropyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1071);-   (2-70).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(3-methylbut-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1095);-   (2-71).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-(3,3-dimethylbut-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1109);-   (2-72).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3-(tert-butyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1085);-   (2-73).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1072);-   (2-74).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1069);-   (2-75).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-(cyclopropylethynyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1093);-   (2-76).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(prop-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1067);-   (2-77).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-(but-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1081);-   (2-78).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-3,5-dimethyl-1H-pyrazole-4-carbonitrile    (1082);-   (2-79).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-fluoro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1075);-   (2-80).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-dicyclopropyl-4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1154);-   (2-81).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-dimethyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1125);-   (2-82).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,5-diethyl-4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1130);-   (2-83).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-18-(4-((3-isopropyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1071);-   (2-84).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1110);-   (2-85).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-amino-3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1124);-   (2-86).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((4-amino-3,5-diethyl-1H-pyrazol-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1100);-   (2-87).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-amino-1H-pyrazol-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1044); and-   (2-88).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3-cyclopentyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1097).

TABLE 2′ Formula (1B1-1) Table 2 Compound NMR's (1H NMR (400 Mhz,DMSO-d₆) δ ppm) Example NMR 2-1  0.67-0.96 (m, 26H), 1.17-1.76 (m, 16H), 2.65-3.11 (m, 16 H), 4.38-5.75 (m, 10 H), 6.24-6.26 (m, 1 H), 7.14(d, 2H) 7.22-7.33 (m, 7H), 7.42-7.45 (m, 1 H), 7.75-7.75 (m, 1H) 2-2 0.67-0.96 (m, 26H), 1.18-1.77 (m, 16 H), 1.98 (s, 3H), 2.65-3.11 (m, 16H), 4.38- 5.75 (m, 10 H), 7.13 (d, 2H) 7.22-7.34 (m, 8H), 7.47-7.49 (m,1 H) 2-3  0.65-0.98 (m, 26H), 1.17-1.76 (m, 16 H), 2.66-3.12 (m, 16 H),4.38-5.75 (m, 10 H), 7.16-7.36 (m, 12H), 7.54 (d, 2H), 7.89-7.91 (m, 1H), 8.21-8.24 (m, 1H) 2-5  0.66-0.94 (m, 26H), 1.18-1.76 (m, 16 H),2.66-3.11 (m, 16 H), 4.38-5.74 (m, 10 H), 7.15-7.36 (m, 11H), 7.55-7.60(m, 2H), 7.86-7.89 (m, 1 H), 8.20-8.23 (m, 1H) 2-6  0.67-0.94 (m, 26H),1.18-1.76 (m, 16 H), 2.65-3.11 (m, 16 H), 4.38-5.74 (m, 10 H), 7.21-7.40(m, 11H), 7.58 (d, 2H), 7.90-7.92 (m, 1 H), 8.25-8.28 (m, 1H) 2-7 0.67-0.96 (m, 26H), 1.18-1.76 (m, 16 H), 2.08-2.13 (m, 6 H), 2.66-3.10(m, 16 H), 4.38-5.74 (m, 10 H), 5.85 (s, 1 H), 7.01 (d, 2H) 7.22-7.33(m, 7H) 2-8  0.67-0.96 (m, 26H), 1.17-1.76 (m, 25 H), 2.66-3.12 (m, 16H), 4.39-5.75 (m, 10 H), 7.15 (d, 2H) 7.22-7.33 (m, 8H), 7.54-7.56 (m, 1H) 2-9  0.65-0.96 (m, 26H), 1.11 (t, 3 H), 1.19-1.76 (m, 16 H), 2.40 (q,2H), 2.66-3.12 (m, 16 H), 4.39-5.75 (m, 10 H), 7.14 (d, 2H) 7.23-7.33(m, 8H), 7.50-7.53 (m, 1 H) 2-10 0.67-0.94 (m, 26 H), 1.18-1.76 (m, 16H), 2.67-3.12 (m, 16 H), 4.39-5.75 (m, 10 H), 7.20-7.34 (m, 9 H),8.05-8.07 (m, 1 H), 8.65-8.67 (m, 1H) 2-11 0.67-0.96 (m, 26 H),1.18-1.76 (m, 16 H), 1.84 (s, 3 H), 2.03-2.06 (m, 6 H), 2.67- 3.11 (m,16 H), 4.40-5.75 (m, 10 H), 7.01 (d, 2 H), 7.23-7.34 (m, 7 H) 2-120.67-0.96 (m, 26 H), 1.18-1.76 (m, 19 H), 2.67-3.12 (m, 16 H), 4.19 (q,2 H), 4.39- 5.75 (m, 10 H), 7.22-7.34 (m, 9 H), 7.83-7.85 (m, 1 H),8.39-8.40 (m, 1H) 2-13 0.67-0.96 (m, 26 H), 1.18-1.75 (m, 16 H), 2.34(s, 3 H), 2.67-3.12 (m, 16 H), 4.39- 5.75 (m, 10 H), 7.21-7.34 (m, 9 H),7.91-7.93 (m, 1 H), 8.47-8.49 (m, 1H) 2-14 0.67-0.96 (m, 26 H),1.18-1.76 (m, 16 H), 2.67-3.11 (m, 16 H), 3.55-3.62 (m, 8 H), 4.39-5.75(m, 10 H), 7.21-7.35 (m, 9 H), 7.70-7.71 (m, 1 H), 8.19-8.21 (m, 1H)2-15 0.67-0.96 (m, 26 H), 1.18-1.76 (m, 22 H), 2.67-3.11 (m, 16 H),3.49-3.55 (m, 4 H), 4.40-5.75 (m, 10 H), 7.19-7.33 (m, 9 H), 7.63-7.65(m, 1 H), 8.11-8.13 (m, 1H) 2-16 0.67-0.96 (m, 26 H), 1.18-1.76 (m, 16H), 2.08 (s, 3 H), 2.67-3.11 (m, 16 H), 4.40- 5.75 (m, 10 H), 7.19 (d, 2H), 7.26-7.33 (m, 7 H), 7.92-7.94 (m, 1 H) 2-17 0.68-0.96 (m, 26 H),1.18-1.76 (m, 16 H), 2.08-2.13 (m, 6 H), 2.67-3.10 (m, 16 H), 4.40-5.75(m, 10 H), 7.06 (d, 2 H), 7.24-7.34 (m, 7 H) 2-18 0.67-0.96 (m, 26 H),1.19-1.76 (m, 16 H), 2.67-3.10 (m, 16 H), 4.40-5.75 (m, 10 H), 6.99 (t,1 H), 7.19-7.33 (m, 9 H), 7.67-7.69 (m 1 H), 8.12-8.14 (m, 1 H) 2-190.68-0.96 (m, 26 H), 1.19-1.76 (m, 16 H), 2.66-3.10 (m, 16 H), 4.32 (s,2 H), 4.40- 5.75 (m, 10 H), 7.16 (d, 2 H), 7.22-7.35 (m, 8 H), 7.60-7.63(m, 1 H) 2-20 0.67-0.96 (m, 26 H), 1.18-1.76 (m, 16 H), 2.67-3.10 (m, 16H), 4.40-5.73 (m, 10 H), 7.23-7.35 (m, 9 H), 7.87-7.89 (m, 1 H),8.46-8.48 (m, 1 H) 2-21 0.68-0.96 (m, 26 H), 1.18-1.76 (m, 22 H),2.67-3.10 (m, 20 H), 4.40-5.73 (m, 10 H), 7.21-7.34 (m, 9 H), 7.77-7.79(m, 1 H), 8.44-8.45 (m, 1 H) 2-22 0.67-0.96 (m, 26 H), 1.18-1.76 (m, 16H), 2.67-3.10 (m, 16 H), 4.40-5.75 (m, 10 H), 7.18-7.34 (m, 9 H),7.53-7.55 (m, 1 H), 8.01-8.03 (m, 1 H) 2-23 0.68-0.96 (m, 26 H),1.19-1.76 (m, 16 H), 2.67-3.10 (m, 20 H), 3.64-3.67 (m, 4 H), 4.40-5.75(m, 10 H), 7.23-7.34 (m, 9 H), 7.81-7.83 (m, 1 H), 8.48-8.50 (m, 1 H)2-24 0.67-0.96 (m, 26 H), 1.18-1.75 (m, 20 H), 2.67-3.12 (m, 20 H),4.40-5.75 (m, 10 H), 7.19-7.34 (m, 9 H), 7.86 (s, 1 H), 8.50-8.52 (m, 1H) 2-25 0.67-0.96 (m, 26 H), 1.17-1.75 (m, 16 H), 2.67-3.10 (m, 16 H),4.41-5.75 (m, 10 H), 7.19-7.34 (m, 9 H), 7.53-7.55 (m, 1 H), 8.03-8.05(m, 1 H) 2-26 0.69-0.94 (m, 27 H), 1.23-1.70 (m, 18 H), 2.33-2.36 (m, 2H), 2.67-3.05 (m, 16 H), 4.38-4.41 (m, 1 H), 5.10-5.70 (m, 11 H),7.11-7.13 (m, 2 H), 7.25-7.31 (m, 8 H), 7.51 (s, 1H) 2-27 0.68-0.96 (m,26 H), 1.18-1.75 (m, 16 H), 1.96-2.01 (m, 2 H), 2.67-3.07 (m, 16 H),3.61-3.63 (m, 4 H), 4.40-5.75 (m, 10 H), 7.22-7.34 (m, 9 H), 7.92-7.94(m, 1 H), 8.58-8.60 (m, 1 H) 2-28 0.76-0.94 (m, 24 H), 1.21-1.75 (m, 17H), 2.67-3.05 (m, 16 H), 4.41-4.43 (m, 1 H), 5.03-5.73 (m, 10 H),7.16-7.30 (m, 9 H), 7.46 (bs, 1 H), 7.91 (bs, 1 H) 2-29 0.66-0.96 (m, 24H), 1.23-1.71 (m, 17 H), 2.67-3.06 (m, 16 H), 4.47-4.53 (m, 1 H),5.08-5.73 (m, 10 H), 7.24-7.31 (m, 9 H), 8.26 (s, 1 H), 9.00 (s, 1 H)2-30 0.77-0.95 (m, 24 H), 1.24-1.70 (m, 17 H), 2.68-3.04 (m, 16 H),4.47-4.53 (m, 1 H), 5.02-5.71 (m, 10 H), 6.99-7.31 (m, 11 H), 8.39 (s, 1H) 2-31 0.67-0.95 (m, 24 H), 1.23-1.70 (m, 17 H), 1.94 (s, 3 H),2.67-3.06 (m, 16 H), 4.41-4.43 (m, 1 H), 5.08-5.35 (m, 10 H), 7.13-7.15(m, 2 H), 7.24-7.31 (m, 8 H), 7.90 (s, 1 H), 9.91 (s, 1 H) 2-320.48-0.54 (m, 4 H), 0.67-0.94 (m, 24 H), 1.23-1.73 (m, 17 H), 2.67-3.06(m, 18 H), 4.41-4.43 (m, 1 H), 5.03-5.73 (m, 14 H), 7.03-7.05 (m, 2 H),7.26-7.31 (m, 8 H) 2-34 0.45-0.47 (m, 2 H), 0.65-0.97 (m, 28 H),1.23-1.70 (m, 17 H), 2.67-3.07 (m, 16 H), 4.38-4.42 (m, 1 H), 4.92-5.70(m, 9 H), 7.18-7.31 (m, 9 H), 7.81 (s, 1 H), 8.00-8.01 (m, 1 H), 8.14(s, 1 H) 2-35 0.65-0.98 (m, 24 H), 1.20-1.80 (m, 18 H), 2.65-3.15 (m, 16H), 3.45-3.55 (m, 2 H), 4.40-4.45 (m, 1 H) 4.58 (t, J = 5.2 Hz, 1 H),5.00-5.85 (m, 11 H), 7.10-7.30 (m, 10 H) 7.52 (s, 1 H) 2-36 0.65-1.00(m, 24 H), 1.15-1.80 (m, 18 H), 2.65-3.15 (m, 19 H), 4.35-4.42 (m, 1 H),5.00-5.80 (m, 9 H), 7.15-7.40 (m, 9 H), 7.69 (s, 2 H), 9.15 (s, 1 H)2-37 0.66-0.95 (m, 26 H), 1.16-1.76 (m, 16 H), 2.64-3.09 (m, 16 H),4.40-5.77 (m, 10 H), 7.23-7.42 (m, 7 H), 7.56-7.60 (m, 2 H), 8.12-8.15(m, 1 H), 8.39 (s, 2 H), 8.80 (d, 1 H), 8.93-8.96 (m, 1 H), 9.58 (s, 1H) 2-38 0.67-0.96 (m, 26 H), 1.18-1.75 (m, 22 H), 1.88-1.96 (m, 2 H),2.67-3.10 (m, 17 H), 4.40-5.75 (m, 10 H), 7.12 (d, 2 H), 7.23-7.33 (m, 8H), 7.52 (s, 1 H) 2-39 0.60-1.04 (m, 27 H) 1.16-1.78 (m, 18 H) 2.66-3.13(m, 16 H) 3.84 (q, J = 6.97 Hz, 2 H) 4.35-4.49 (m, 3 H) 5.00-5.56 (m, 9H) 5.64-5.76 (m, 1 H) 7.10-7.31 (m, 9 H) 7.44-7.51 (m, 1 H) 2-400.68-0.96 (m, 26 H), 1.18-1.77 (m, 20 H), 2.29 (s, 3 H), 2.39 (s, 3 H),2.67-3.10 (m, 20 H), 4.40-5.75 (m, 10 H), 7.06 (d, 2 H), 7.23-7.33 (m, 7H) 2-41 0.62-0.99 (m, 27 H), 1.14-1.82 (m, 15 H), 2.64-3.13 (m, 16 H),4.37-4.49 (m, 1 H), 4.97-5.78 (m, 9 H), 7.19 (br d, 2 H), 7.22-7.36 (m,7 H), 7.52 (s, 1 H), 7.94- 7.99 (m, 1 H) 2-42 0.62-0.95 (m, 24 H),1.15-1.75 (m, 18 H), 2.6-3.1 (m, 16 H), 4.32-4.39 (m, 4 H), 4.90-5.80(m, 12 H), 6.13 (s, 1 H), 7.05-7.15 (m, 2 H), 7.18-7.35 (m, 7 H) 2-430.68-0.95 (m, 24 H), 1.15-1.80 (m, 18 H), 1.95-2.01 (m, 9 H), 2.65-3.20(m, 16 H), 4.38-4.48 (m, 1 H), 5.00-5.80 (m, 9 H), 7.00-7.08 (m, 2 H),7.20-7.35 (m, 7 H), 8.90 (s, 1 H) 2-44 0.72-0.96 (m, 24 H), 1.17-1.70(m, 17 H), 1.96 (s, 3 H), 2.00 (s, 3 H), 2.67-3.08 (m, 16 H), 4.35-4.45(m, 1 H), 5.01-5.75 (m, 10 H), 6.95-6.97 (m, 2 H), 7.23- 7.31 (m, 7 H),7.55 (brs, 1 H) 2-45 0.69-0.95 (m, 24 H), 1.12-1.75 (m, 17 H), 2.65-3.05(m, 16 H), 4.35-4.45 (m, 1 H), 5.01-5.75 (m, 10 H), 7.24-7.30 (m, 8 H),7.71-7.73 (m, 2 H), 8.18 (s, 1 H), 8.57-8.58 (m, 1 H), 8.67-8.68 (m, 1H), 9.03 (s, 1 H) 2-46 0.65-0.95 (m, 24 H), 1.12-1.78 (m, 17 H),2.65-3.05 (m, 16 H), 4.35-4.45 (m, 1 H), 5.01-5.75 (m, 10 H), 7.26-7.30(m, 8 H), 8.14 (s, 1 H), 8.40 (s, 2 H), 8.49- 8.53 (m, 2 H), 8.96 (s, 1H) 2-47 0.60-0.95 (m, 24 H), 1.10-1.70 (m, 17 H), 2.65-3.05 (m, 16 H),4.35-4.45 (m, 1 H), 5.01-5.75 (m, 10 H), 7.15-7.31 (m, 10 H), 7.61-7.63(m, 1 H), 7.70-7.80 (m, 1 H), 8.02 (s, 1 H), 8.34 (s, 1 H), 8.47 (s, 1H) 2-48 0.67-0.96 (m, 24 H), 1.24-1.73 (m, 26 H), 2.68-3.06 (m, 16 H),3.92-3.94 (m, 2 H), 4.37-4.48 (m, 1 H), 5.01-5.75 (m, 10 H), 7.11-7.15(m, 3 H), 7.25-7.31 (m, 8 H), 7.57-7.58 (m, 1 H) 2-49 0.68-0.96 (m, 24H), 1.23-1.71 (m, 16 H), 2.27 (s, 3 H), 2.34 (s, 3 H), 2.67-3.06 (m, 16H), 4.401-4.43 (m, 1 H), 5.01-5.73 (m, 11 H), 7.07-7.10 (m, 4 H), 7.24-7.31 (m, 7 H) 2-50 0.68-0.96 (m, 24 H), 1.23-1.73 (m, 16 H), 2.10-2.12(m, 6 H), 2.67-3.06 (m, 16 H), 4.40-4.42 (m, 1H), 5.02-5.70 (m, 11 H),7.05-7.06 (m, 2 H), 7.27-7.31 (m, 7 H) 2-51 0.72-0.94 (m, 24 H),1.23-1.70 (m, 16 H), 2.67-3.04 (m, 16 H), 3.97 (s, 1 H), 4.40-4.43 (m, 1H), 5.03-5.73 (m, 11 H), 7.17-7.30 (m, 9 H), 7.63 (s, 1 H), 8.09- 8.10(m, 1 H) 2-52 0.67-0.96 (m, 24 H), 1.23-1.70 (m, 17 H), 1.79 (s, 3 H),2.68-3.06 (m, 16 H), 4.04 (d, J = 5.6 Hz, 2 H), 4.35-4.45 (m, 1 H),5.01-5.75 (m, 10 H), 7.15-7.17 (m, 2 H), 7.26-7.33 (m, 8 H), 7.61-7.62(m, 1 H), 8.05-8.15 (m, 1 H) 2-53 0.70-0.94 (m, 24 H), 1.12-1.80 (m, 17H), 2.67-3.05 (m, 16 H), 4.35-4.48 (m, 1 H), 5.01-5.75 (m, 10 H), 6.97(s, 1 H), 7.15-7.31 (m, 9 H), 7.52 (s, 1 H), 7.83 (s, 1 H), 8.14 (s, 1H) 2-54 0.77-0.94 (m, 24 H), 1.05-1.71 (m, 30 H), 2.66-3.05 (m, 16 H),4.40-4.42 (m, 1 H), 5.01-5.72 (m, 11 H), 5.92 (s, 1 H), 6.97-6.99 (m, 2H), 7.24-7.31 (m, 7 H) 2-55 0.70-0.95 (m, 24 H), 1.23-1.70 (m, 16 H),2.66-3.06 (m, 16 H), 4.40-4.42 (m, 1 H), 5.02-5.73 (m, 11 H), 7.11-7.13(m, 2 H), 7.25-7.31 (m, 7 H), 7.63 (s, 1 H) 2-56 0.63-1.00 (m, 27 H),1.11-1.82 (m, 15 H), 2.60-3.14 (m, 16 H), 4.37-4.49 (m, 1 H), 4.96-5.78(m, 9 H), 6.69-6.75 (m, 1 H), 7.18-7.33 (m, 10 H), 7.34-7.42 (m, 2 H),7.77 (d, 2 H), 7.81-7.87 (m, 1 H) 2-57 0.63-0.99 (m, 27 H), 1.14-1.79(m, 15 H), 2.63-3.15 (m, 16 H), 4.38-4.46 (m, 1 H), 4.97-5.78 (m, 9 H),6.35-6.42 (m, 1 H), 7.16-7.22 (m, 2 H), 7.22-7.35 (m, 7 H), 7.81-7.88(m, 1 H) 2-58 0.61-0.99 (m, 27 H), 1.14-1.80 (m, 15 H), 2.62-3.13 (m, 16H), 4.37-4.46 (m, 1 H), 4.97-5.78 (m, 9H), 6.69-6.76 (m, 1 H), 7.18-7.36(m, 9 H), 8.03-8.09 (m, 1 H) 2-59 0.69-0.95 (m, 24 H), 1.23-1.73 (m, 17H), 2.67-3.05 (m, 16 H), 3.86-3.87 (m, 2 H), 4.41-4.43 (m, 1 H),5.10-5.73 (m, 10 H), 7.17-7.31 (m, 9 H), 7.54 (s, 1 H), 7.85 (s, 1 H),8.06 (brs, 3 H) 2-60 0.69-0.96 (m, 26 H), 1.19-1.76 (m, 22 H), 2.27 (s,3 H), 2.36 (s, 3 H), 2.67-3.11 (m, 20 H), 4.39-5.75 (m, 10 H), 7.06 (d,2 H), 7.22-7.34 (m, 7 H) 2-61 0.67-0.96 (m, 26 H), 1.19-1.76 (m, 16 H),1.83-1.92 (m, 2 H), 2.36-2.51 (m, 4 H), 2.67-3.11 (m, 16 H), 4.40-5.76(m, 10 H), 5.83 (s, 1 H), 7.16 (d, 2 H), 7.23-7.34 (m, 7 H), 7.57 (s, 1H), 7.77-7.79 (m, 1 H) 2-62 0.70-0.95 (m, 24 H), 1.23-1.70 (m, 16 H),2.66-3.07 (m, 16 H), 4.40-4.42 (m, 1 H), 5.12-5.73 (m, 11 H), 7.23-7.37(m, 9 H), 7.99 (s, 1 H) 2-63 0.70-0.95 (m, 24 H), 1.24-1.72 (m, 16 H),2.68-3.05 (m, 16 H), 4.39-4.43 (m, 1 H), 5.03-5.73 (m, 11 H), 7.25-7.30(m, 11 H), 7.71 (s, 1 H), 8.26 (s, 1 H) 2-64 0.68-0.96 (m, 24 H),1.24-1.70 (m, 16 H), 2.67-3.06 (m, 16 H), 4.36-4.40 (m, 1 H), 4.98-5.33(m, 11 H), 7.20-7.46 (m, 14 H), 7.71 (s, 1 H), 8.15-8.17 (m, 1 H) 2-660.50-0.54 (m, 2 H), 0.68-0.96 (m, 28 H), 1.19-1.79 (m, 17 H), 2.67-3.10(m, 16 H), 4.40-5.75 (m, 10 H), 5.90 (s, 1 H), 7.06 (d, 2 H) 7.23-7.34(m, 8 H) 2-67 0.64-0.95 (m, 26 H), 1.19-1.76 (m, 16 H), 2.67-3.10 (m, 16H), 4.39-5.75 (m, 10 H), 6.45 (s, 1 H), 6.90 (d, 2H) 7.21-7.46 (m, 12H), 7.57 (s, 1 H) 2-68 0.69-0.96 (m, 26 H), 1.19-1.75 (m, 25 H),2.66-3.10 (m, 16 H), 4.40-5.75 (m, 10 H), 6.09 (s, 1 H), 6.89 (d, 2 H)7.22-7.37 (m, 8 H) 2-69 0.69-0.97 (m, 26 H), 1.07 (d, 6 H), 1.20-1.74(m, 16 H), 2.66-3.10 (m, 17 H), 4.40- 5.75 (m, 10 H), 6.11 (s, 1 H),7.00 (d, 2 H) 7.23-7.38 (m, 8 H) 2-70 0.72-0.87 (m, 24 H), 1.14-1.70 (m,22 H), 2.67-3.04 (m, 16 H), 4.41-4.43 (m, 1 H), 5.03-5.73 (m, 12 H),7.15-7.17 (m, 2 H), 7.29-7.31 (m, 7 H), 7.51 (brs, 1 H), 7.94 (brs, 1 H)2-71 0.69-0.96 (m, 24 H), 1.23-1.70 (m, 24 H), 2.67-3.06 (m, 16 H),4.40-4.43 (m, 1 H), 5.02-5.73 (m, 12 H), 7.15-7.17 (m, 2 H), 7.24-7.31(m, 7 H), 7.49 (brs, 1 H), 7.92-7.93 (m, 1 H) 2-72 0.67-0.96 (m, 24 H),1.22-1.54 (m, 24 H), 2.67-3.06 (m, 16 H), 4.41-4.43 (m, 1 H), 5.01-5.75(m, 12 H), 6.10-6.11 (m, 1 H), 7.10-7.12 (m, 2 H), 7.25-7.31 (m, 7 H),7.55-7.57 (m, 1 H) 2-74 0.70-0.96 (m, 28 H), 1.22-1.82 (m, 16 H),2.67-3.06 (m, 16 H), 4.39-4.42 (m, 1 H), 5.09-5.92 (m, 12 H), 7.11-7.31(m, 10 H), 7.57 (brs, 1 H) 2-75 0.63-0.94 (m, 28 H), 1.23-1.70 (m, 16H), 2.67-3.04 (m, 16 H), 4.38-4.41 (m, 1 H), 5.03-5.70 (m, 12 H),7.16-7.31 (m, 9 H), 7.50 (s, 1 H), 7.93 (s, 1 H) 2-76 0.74-0.94 (m, 23H), 1.23-1.70 (m, 19 H), 1.95 (s, 3H), 2.67-3.04 (m, 16 H), 4.35- 4.45(m, 1 H), 5.10-5.69 (m, 9 H), 7.16 (d, J = 7.6 Hz, 2 H), 7.29-7.31 (m, 7H), 7.51 (s, 1 H), 7.94-7.96 (m, 1H) 2-77 0.69-0.98 (m, 24 H), 1.10 (t,J = 7.4 Hz, 3H), 1.23-1.69 (m, 18 H), 2.33-2.37 (m, 2 H), 2.67-3.31 (m,16 H), 4.31-4.45 (m, 1 H), 5.1-5.8 (m, 9 H), 7.16 (d, J = 7.7 Hz, 2 H),7.27-7.31 (m, 7 H), 7.51 (s, 1 H), 7.94-7.95 (m, 1 H) 2-78 0.67-0.95 (m,26 H), 1.23-1.67 (m, 16 H), 2.21 (s, 3 H), 2.32 (s, 3 H), 2.67-3.37 (m,16 H), 4.31-4.45 (m, 1 H), 5.08-5.8 (m, 9 H), 7.11 (d, J = 7.8 Hz, 2 H),7.25- 7.31 (m, 7 H) 2-79 0.68-0.95 (m, 24 H), 1.23-1.72 (m, 18 H),2.07-2.09 (m, 6 H), 2.67-3.31 (m, 16 H), 4.31-4.45 (m, 1H), 5.03-5.73(m, 9H), 7.03 (d, J = 7.8 Hz, 2H), 7.25-7.31 (m, 7 H) 2-80 0.70-0.93 (m,31 H), 1.06-1.27 (m, 10 H), 1.42-1.78 (m, 9 H), 2.33-2.45 (m, 2 H),2.67-3.05 (m, 16 H), 4.40-4.42 (m, 1 H), 5.02-5.70 (m, 9 H), 7.08-7.09(m, 2 H), 7.28-7.30 (m, 7 H) 2-81 0.86-0.95 (m, 26 H), 1.27-1.70 (m, 16H), 2.20 (s, 3H), 2.27 (s, 3 H), 2.67-3.31 (m, 16 H), 4.40-4.45 (m, 1H), 5.10-5.69 (m, 9 H), 7.08-7.09 (m, 2 H), 7.25- 7.30 (m, 7 H) 2-820.79-0.96 (m, 28 H), 1.17-1.71 (m, 20 H), 2.66-3.05 (m, 20 H), 4.39-4.42(m, 1 H), 5.11-5.73 (m, 9 H), 7.15-7.17 (m, 2 H), 7.25-7.31 (m, 7 H)2-83 0.70-0.94 (m, 26 H), 1.06-1.7 (m, 22 H), 2.67-3.15 (m, 17 H),4.35-4.45 (m, 1 H), 5.02-5.71 (m, 9 H), 6.06-6.07 (m, 1 H), 7.12 (d, J =7.1 Hz, 2 H), 7.25-7.3 (m, 7 H), 7.59 (s, 1 H) 2-84 0.65-0.94 (m, 26 H),1.22-1.70 (m, 16 H), 2.67-3.05 (m, 16 H), 4.03 (s, 3 H), 4.35-4.45 (m, 1H), 5.02-5.72 (m, 9 H), 7.23-7.31 (m, 9 H), 7.76 (s, 1 H), 8.09- 8.14(m, 2 H) 2-85 0.54-0.94 (m, 32 H), 1.20-1.73 (m, 18 H), 2.67-3.05 (m, 16H), 4.40-4.43 (m, 1 H), 5.04-5.70 (m, 13 H), 6.92-7.31 (m, 9 H) 2-860.65-0.94 (m, 29 H), 1.11 (t, J = 7.2 Hz, 3 H), 1.24-1.70 (m, 16 H),2.42-2.44 (m, 4H), 2.67-3.06 (m, 16H), 4.35-4.45 (m, 1H), 5.01-5.75 (m,11 H), 6.95-7.31 (m, 9 H) 2-87 0.68-0.98 (m, 26 H), 1.20-1.78 (m, 16 H),2.64-3.13 (m, 16 H), 4.39-4.43 (m, 1 H), 4.51 (bs, 2 H), 4.96-5.74 (m, 9H), 7.08-7.39 (m, 11 H) 2-88 0.65-0.96 (m, 26 H), 1.22-1.91 (m, 22 H),2.67-3.06 (m, 17 H), 4.35-4.45 (m, 1 H), 5.09-5.70 (m, 11 H), 6.05 (s, 1H), 7.11-7.13 (m, 2 H), 7.25-7.31 (m, 7 H), 7.58-7.60 (m, 1 H)

The following Formula (1C1-1) compounds (meta/para) described in Table 3were prepared in accordance with the schemes and examples describedherein.

TABLE 3 Formula (1C1-1) Compounds # 3 and 3′ 4 and 4′ 5 and 5′ 3-1  H HH 3-2  H methyl H 3-3  H Br H 3-4  H phenyl H 3-5  H pyridin-4-yl H 3-6 H 4-F-phenyl H 3-7  H 4-Cl-phenyl H 3-8  methyl H methyl 3-9  H t-butylH 3-10 H ethyl H 3-11 H —CN H 3-12 methyl methyl methyl 3-13 H—C(O)OCH₂CH₃ H 3-14 H isopropyl H 3-15 H —C(O)CH₃ H 3-16 H

H 3-17 H

H 3-18 H

H 3-19 H I H 3-20 H

H 3-21 H propyl H 3-22

H

3-23 methyl ethyl methyl 3-24 H

H 3-25 H

H 3-26 methyl Cl methyl 3-27 H methoxy H 3-28 methyl propyl methyl 3-29H —CF₃ H 3-30 isopropyl H isopropyl 3-31 H —C(O)N(CH₃)₂ H 3-32 H—S(O)₂CH₃ H 3-33 H —SCH(CH₃)₂ H 3-34 methyl —CH₂CH₂OH methyl 3-35 —CF₃ H—CF₃ 3-36 —CN H —CN 3-37 H F H 3-38 H pyridin-2-yl H 3-39 H —OH H 3-40 H—NHC(O)CH₃ H 3-41 H —NO₂ H 3-42 H

H 3-43 H —CH₂CH₂OH H 3-44 —CH₂OH H —CH₂OH 3-45 methyl —NHC(O)CH₃ methyl3-46 H

H

The following Formula (1C1-1) compound and example ifs refer to thosecompounds depicted in Table 3. In one aspect of the invention, areFormula (1C1-1) compounds selected from the group consisting of:

-   (3-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-[[3-(pyrazol-1-ylmethyl)phenyl]methyl]-24-[[4-(pyrazol-1-ylmethyl)phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1110);-   (3-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-[[3-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-24-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1138);-   (3-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[3-[(4-bromopyrazol-1-yl)methyl]phenyl]methyl]-18-[[4-[(4-bromopyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1268);-   (3-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-[[3-[(4-phenylpyrazol-1-yl)methyl]phenyl]methyl]-24-[[4-[(4-phenylpyrazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1262);-   (3-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(pyridin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(pyridin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (3-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[3-[[4-(4-fluorophenyl)pyrazol-1-yl]methyl]phenyl]methyl]-18-[[4-[[4-(4-fluorophenyl)pyrazol-1-yl]methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1298);-   (3-7).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[3-[[4-(4-chlorophenyl)pyrazol-1-yl]methyl]phenyl]methyl]-18-[[4-[[4-(4-chlorophenyl)pyrazol-1-yl]methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1332);-   (3-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (3-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[3-[(4-tert-butylpyrazol-1-yl)methyl]phenyl]methyl]-18-[[4-[(4-tert-butylpyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1222);-   (3-10)    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[3-[(4-ethylpyrazol-1-yl)methyl]phenyl]methyl]-18-[[4-[(4-ethylpyrazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1166);-   (3-11).    1-(3-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-cyano-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-4-carbonitrile    (1159);-   (3-12).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((3,4,5-trimethyl-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((3,4,5-trimethyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (3-13). ethyl    1-(3-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-(ethoxycarbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate    (1253);-   (3-14).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(3-((4-isopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-isopropyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (3-15).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-acetyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-acetyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1193);-   (3-16).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1304);-   (3-17).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1332);-   (3-18).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1189);-   (3-19).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1361);-   (3-20).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-(1H-pyrrol-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-(1H-pyrrol-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (ESI-MS m/z: 1240.4[M+H]+);-   (3-21).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (3-22).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1270);-   (3-23).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-ethyl-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-ethyl-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1222);-   (3-24).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(piperidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(piperidin-1-ylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1404);-   (3-25).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(morpholinosulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(morpholinosulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1408);-   (3-26).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1234);-   (3-27).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(3-((4-methoxy-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-methoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1169);-   (3-28).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((3,5-dimethyl-4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3,5-dimethyl-4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (3-29).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1245);-   (3-30).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((3,5-diisopropyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3,5-diisopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1278);-   (3-31).    1-(3-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-(dimethylcarbamoyl)-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide    (1252);-   (3-32).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(methylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(methylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1266);-   (3-33).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(3-((4-(isopropylthio)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-(isopropylthio)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1258);-   (3-34).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1254);-   (3-35).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1381);-   (3-36).    1-(3-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((3,5-dicyano-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile    (1209);-   (3-37).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1145);-   (3-38).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (3-39).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-hydroxy-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-hydroxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1141);-   (3-40).    N-(1-(3-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-acetamido-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazol-4-yl)acetamide    (1223);-   (3-41).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1199);-   (3-42).    N-cyclopropyl-1-(3-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-(cyclopropylcarbamoyl)-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide    (1276);-   (3-43).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((4-(2-hydroxyethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((4-(2-hydroxyethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197);-   (3-44).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((3,5-bis(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3,5-bis(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1229);-   (3-45).    N-(1-(3-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((4-acetamido-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetamide    (1280); and-   (3-46).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(3-((4-(phenylethynyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((4-(phenylethynyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1310).

TABLE 3′ Formula (1C1-1) Table 3 Compound NMR's (1H NMR (400 Mhz,DMSO-d₆) δ ppm) Example NMR 3-1  0.66-0.92 (m, 26H), 1.16-1.79 (m, 16H), 2.64-3.10 (m, 16 H), 4.39-5.73 (m, 12 H), 6.24-6.26 (m, 2 H),7.04-7.30 (m, 8H), 7.42-7.44 (m, 2 H), 7.75-7.78 (m, 2H) 3-2  0.66-0.92(m, 26H), 1.13-1.70 (m, 16 H), 1.96-1.98 (m, 6H) 2.67-3.08 (m, 16 H),4.39-5.74 (m, 12 H), 6.24-6.26 (m, 2 H), 7.02-7.28 (m, 10H), 7.47-7.52(m, 2 H) 3-3  0.65-0.96 (m, 26H), 1.15-1.76 (m, 16 H), 2.66-3.11 (m, 16H), 4.39-5.73 (m, 12 H), 7.12-7.34 (m, 9H), 7.54-7.56 (m, 2 H),8.02-8.04 (m, 2H) 3-4  0.62-0.94 (m, 26H), 1.12-1.78 (m, 16 H),2.63-3.10 (m, 16 H), 4.38-5.74 (m, 12 H), 7.14-7.36 (m, 14 H), 7.54 (d,4 H), 7.87-7.91 (m, 2 H), 8.20-8.25 (m, 2H) 3-6  0.64-0.95 (m, 26H),1.15-1.75 (m, 16 H), 2.62-3.11 (m, 16 H), 4.38-5.75 (m, 12 H), 7.14-7.37(m, 12 H), 7.53-7.62 (m, 4 H), 7.87-7.91 (m, 2 H), 8.20-8.24 (m, 2H)3-7  0.64-0.94 (m, 26H), 1.15-1.73 (m, 16 H), 2.65-3.12 (m, 16 H),4.38-5.75 (m, 12 H), 7.14-7.43 (m, 12 H), 7.56-7.61 (m, 4 H), 7.91-7.93(m, 2 H), 8.26-8.30 (m, 2H) 3-8  0.66-0.95 (m, 26H), 1.17-1.76 (m, 16H), 2.06-2.16 (m, 12 H) 2.67-3.09 (m, 16 H), 4.39-5.73 (m, 12 H),5.83-5.86 (m, 2 H), 6.88-7.04 (m, 4 H), 7.14-7.28 (m, 4 H) 3-9 0.65-0.95 (m, 26H), 1.15-1.75 (m, 34 H), 2.67-3.10 (m, 16 H), 4.39-5.73(m, 12 H), 7.07-7.34 (m, 10H), 7.54-7.57 (m, 2 H) 3-10 0.65-0.96 (m,26H), 1.07-1.75 (m, 22 H), 2.40 (q, 4H) 2.67-3.09 (m, 16 H), 4.38-5.73(m, 12 H), 7.05-7.32 (m, 10H), 7.50-7.55 (m, 2 H) 3-11 0.64-0.95 (m,26H), 1.17-1.76 (m, 16 H), 2.67-3.11 (m, 16 H), 4.39-5.76 (m, 12 H),7.14-7.36 (m, 8 H), 8.05-8.08 (m, 2 H), 8.65-8.68 (m, 2 H) 3-120.66-0.95 (m, 26H), 1.19-1.75 (m, 16 H), 1.84 (s, 6 H), 2.04-2.09 (m, 12H), 2.68- 3.09 (m, 16H), 4.39-5.72 (m, 12H), 6.89-6.94 (m, 1H), 7.02 (d,2H), 7.15-7.28 (m, 5 H) 3-13 0.64-0.96 (m, 26H), 1.17-1.76 (m, 22 H),2.67-3.11 (m, 16 H), 4.19 (q, 4H) 4.39-5.75 (m, 12 H), 7.15-7.38 (m, 8H), 7.84-7.86 (m, 2 H), 8.39-8.42 (m, 2 H) 3-14 0.65-0.95 (m, 26H), 1.13(d, 12 H), 1.18-1.76 (m, 16 H), 2.67-3.09 (m, 18 H), 4.39- 5.72 (m, 12H), 7.06-7.32 (m, 10 H), 7.51-7.55 (m, 2 H) 3-15 0.65-0.95 (m, 26H),1.17-1.76 (m, 16 H), 2.33-2.36 (m, 6 H), 2.68-3.11 (m, 16 H), 4.39-5.75(m, 12 H), 7.14-7.38 (m, 8 H), 7.91-7.93 (m, 2 H), 8.47-8.50 (m, 2 H)3-16 0.65-0.95 (m, 26H), 1.18-1.94 (m, 24 H), 2.68-3.10 (m, 16 H),3.40-3.43 (m, 4 H), 3.57-3.65 (m, 4 H), 4.39-5.75 (m, 12 H), 7.12-7.35(m, 8 H), 7.77-7.80 (m, 2 H), 8.27-8.29 (m, 2 H) 3-17 0.64-0.95 (m,26H), 1.19-1.76 (m, 28 H), 2.68-3.10 (m, 16 H), 3.52-3.54 (m, 8 H),4.39-5.74 (m, 12 H), 7.13-7.37 (m, 8 H), 7.64 (s, 2 H), 8.12-8.15 (m, 2H) 3-18 0.42-0.43 (m, 4 H), 0.66-0.94 (m, 28 H), 1.24-1.75 (m, 19 H),2.67-3.04 (m, 16 H), 4.37-4.48 (m, 1 H), 5.01-5.75 (m, 12 H), 7.07-7.52(m, 12 H) 3-19 0.64-0.93 (m, 24 H), 1.23-1.72 (m, 17 H), 2.68-3.04 (m,16 H), 4.37-4.45 (m, 1 H), 5.03-5.76 (m, 12 H), 7.12-7.33 (m, 8 H), 7.52(s, 2 H), 7.96-7.98 (m, 2 H) 3-21 0.79-0.94 (m, 28 H), 1.24-1.52 (m, 20H), 2.33-2.36 (m, 4 H), 2.68-3.03 (m, 17 H), 4.41-4.48 (m, 1H),5.10-5.74 (m, 14H), 7.11-7.26 (m, 10 H), 7.51-7.53 (m, 2 H) 3-220.44-0.58 (m, 8 H), 0.67-0.95 (m, 32 H), 1.23-1.76 (m, 20 H), 2.67-3.03(m, 15 H), 4.41-4.43 (m, 1 H), 5.09-5.68 (m, 14 H), 7.03-7.05 (m, 1 H),7.17-7.19 (m, 3 H), 7.22-7.27 (m, 6 H) 3-23 0.73-1.00 (m, 26 H),1.23-1.70 (m, 20 H), 2.04-2.07 (m, 12 H), 2.25-2.33 (m, 5 H), 2.68-3.05(m, 16 H), 4.41-4.43 (m, 1 H), 5.09-5.68 (m, 12 H), 6.98-7.00 (m, 1 H),7.13-7.17 (m, 2 H), 7.18-7.26 (m, 5 H) 3-24 0.64-0.95 (m, 26H),1.22-1.76 (m, 28 H), 2.68-3.11 (m, 24 H), 4.39-5.75 (m, 12 H), 7.13-7.37(m, 8 H), 7.78-7.80 (m, 2 H), 8.44-8.47 (m, 2 H) 3-25 0.65-0.95 (m,26H), 1.18-1.76 (m, 16 H), 2.68-3.11 (m, 24 H), 3.64-3.67 (m, 8 H),4.40-5.75 (m, 12 H), 7.14-7.38 (m, 8 H), 7.82-7.84 (m, 2 H), 8.49-8.51(m, 2 H) 3-26 0.65-0.94 (m, 24 H), 1.23-1.68 (m, 17 H), 2.09-2.16 (m, 12H), 2.67-3.04 (m, 16 H), 4.39-4.42 (m, 1 H), 5.11-5.68 (m, 12 H),7.04-7.29 (m, 8 H) 3-27 0.69-0.97 (m, 24 H), 1.23-1.71 (m, 16 H),2.67-3.03 (m, 16 H), 3.62 (s, 6 H), 4.39-4.42 (m, 1 H), 4.95-5.69 (m, 13H), 7.07-7.52 (m, 12 H) 3-28 0.69-0.95 (m, 30 H), 1.23-1.69 (m, 20 H),2.02-2.06 (m, 12 H), 2.22-2.26 (m, 4 H), 2.67-2.88 (m, 13 H), 2.98-3.09(m, 3 H), 4.39-4.15 (m, 1 H), 4.95-5.75 (m, 13 H), 6.85-6.91 (m, 1 H),6.96-6.98 (m, 2 H), 7.15-7.25 (m, 5 H) 3-29 1H NMR (400 MHz, CDCl₃) δ:0.80-0.98 (m, 24 H), 1.38-1.70 (m, 16 H), 2.62- 3.12 (m, 16 H),4.40-4.42 (m, 1 H), 5.06-5.62 (m, 13 H), 7.17-7.30 (m, 8 H), 7.61 (s, 2H), 7.71 (s, 2 H) 3-30 1H NMR (400 MHz, CDCl₃) δ: 0.79-0.96 (m, 28 H),1.09-1.13 (m, 12 H), 1.24- 1.26 (m, 12 H), 1.37-1.44 (m, 6 H), 1.62-1.71(m, 6 H), 2.69-2.80 (m, 12 H), 2.93- 3.04 (m, 8 H), 4.40-4.42 (m, 1 H),5.04-5.59 (m, 13 H), 5.88 (s, 2 H), 6.92-7.16 (m, 8 H) 3-31 0.77-0.94(m, 24 H), 1.23-1.70 (m, 16 H), 2.67-3.11 (m, 28 H), 4.40-4.42 (m, 1 H),5.08-5.89 (m, 13 H), 7.20-7.35 (m, 8 H), 7.72 (s, 2 H), 8.20-8.22 (m, 2H) 3-32 0.65-0.93 (m, 24 H), 1.24-1.71 (m, 16 H), 2.68-3.05 (m, 16 H),3.18 (s, 6 H), 4.40-4.42 (m, 1 H), 5.10-581 (m, 13 H), 7.21-7.40 (m, 8H), 7.92 (s, 2 H), 8.49- 8.53 (m, 2 H) 3-33 0.65-0.93 (m, 24 H),1.12-1.13 (m, 12 H), 1.23-1.66 (m, 18 H), 2.67-3.03 (m, 16 H), 4.41-4.43(m, 1 H), 5.11-5.67 (m, 13 H), 7.15-7.28 (m, 8 H), 7.46 (s, 2 H),7.91-7.94 (m, 2 H) 3-34 0.66-0.95 (m, 24 H), 1.23-1.70 (m, 16 H),2.04-2.08 (m, 12 H), 2.40-2.44 (m, 4 H), 2.68-3.02 (m, 16 H), 3.31-3.34(m, 4 H), 4.39-4.40 (m, 1 H), 5.09-5.68 (m, 15 H), 6.87-6.92 (m, 1 H),6.99-7.01 (m, 2 H), 7.13-7.27 (m, 5 H) 3-35 0.71-0.92 (m, 24 H),1.23-1.69 (m, 16 H), 2.67-3.06 (m, 16 H), 4.39-4.41 (m, 1 H), 5.03-5.71(m, 13 H), 7.01-7.05 (m, 1 H), 7.11-7.13 (m, 2 H), 7.26-7.34 (m, 5 H),7.64 (brs, 2 H) 3-36 0.65-0.94 (m, 24 H), 1.23-1.70 (m, 17 H), 2.67-3.07(m, 16 H), 4.35-4.45 (m, 1 H), 5.01-5.81 (m, 12 H), 7.13-7.36 (m, 8 H),7.99-8.01 (m, 2 H) 3-37 0.74-0.94 (m, 24 H), 1.23-1.75 (m, 17 H),2.68-3.06 (m, 16 H), 4.35-4.45 (m, 1 H), 5.01-5.73 (m, 12 H), 7.11-7.47(m, 10 H), 7.91-7.94 (m, 2 H) 3-38 0.66-0.92 (m, 24 H), 1.24-1.69 (m, 17H), 2.65-3.11 (m, 16 H), 4.37-4.43 (m, 1 H), 5.01-5.75 (m, 12 H),7.14-7.38 (m, 10 H), 7.62-7.64 (m, 2 H), 7.72-7.76 (m, 2 H), 8.02-8.03(m, 2 H), 8.02-8.37 (m, 2 H), 8.47-8.48 (m, 2 H) 3-39 0.65-0.94 (m, 24H), 1.19-1.70 (m, 17 H), 2.68-3.04 (m, 16 H), 4.40-4.43 (m, 1 H),5.10-5.70 (m, 12 H), 6.99-7.25 (m, 12 H), 8.39-8.41 (m, 2 H) 3-400.67-0.94 (m, 24 H), 1.23-1.81 (m, 17 H), 1.94 (s, 6 H), 2.68-3.03 (m,16 H), 4.41-4.43 (m, 1 H), 5.07-5.72 (m, 12 H), 7.08-7.13 (m, 1 H),7.15-7.19 (m, 3 H), 7.24-7.26 (m, 4 H), 7.37 (s, 2 H), 7.89-7.93 (m, 2H), 9.92 (s, 2 H) 3-41 0.64-0.93 (m, 24 H), 1.23-1.71 (m, 17 H),2.68-3.06 (m, 16 H), 4.37-4.48 (m, 1 H), 5.01-5.71 (m, 12 H), 7.22-7.41(m, 8 H), 8.26-8.28 (m, 2 H), 8.99-9.03 (m, 2 H) 3-42 0.44-0.48 (m, 4H), 0.63-0.94 (m, 28 H), 1.23-1.70 (m, 17 H), 2.68-3.04 (m, 18 H),4.37-4.48 (m, 1 H), 5.02-5.70 (m, 12 H), 7.12-7.30 (m, 8 H), 8.01-8.17(m, 6 H) 3-43 0.67-0.95 (m, 26 H), 1.24-1.70 (m, 17 H), 2.69-3.03 (m, 18H), 3.46-3.50 (m, 4 H), 4.37-4.45 (m, 1 H), 4.57-4.60 (m, 2 H),5.08-5.70 (m, 12 H), 7.06-7.28 (m, 10 H), 7.53-7.56 (m, 2 H) 3-440.68-1.00 (m, 24 H), 1.10-1.70 (m, 18 H), 2.60-3.20 (m, 16 H), 4.33-4.43(m, 8 H), 4.9 0-5.80 (m, 16 H), 6.13 (s, 2 H), 6.97-7.23 (m, 8 H) 3-450.67-0.96 (m, 24 H), 1.23-1.61 (m, 18 H), 1.95-1.99 (m, 18 H), 2.65-3.15(m, 16 H), 4.40-4.50 (m, 1 H), 4.95-5.80 (m, 11 H), 6.80-7.10 (m, 3 H),7.15-7.35 (m, 5 H), 8.95 (s, 2 H) 3-46 0.66-0.94 (m, 24 H), 1.23-1.69(m, 16 H), 2.67-3.07 (m, 16 H), 4.38-4.40 (m, 1 H), 4.99-5.74 (m, 13 H),7.14-7.46 (m, 18 H), 7.71 (brs, 2 H), 8.15-8.18 (m, 2 H)

The following Formula (1D1-1) compounds (meta/meta; bis) described inTable 4 were prepared in accordance with the schemes and examplesdescribed herein.

TABLE 4 Formula (1D1-1) Symmetrical Compounds # 3 and 3′ 4 and 4′ 5 and5′ 4-1  H H H 4-2  H Br H 4-3  H I H 4-4  H propyl H 4-5 

H

4-6  methyl ethyl methyl 4-7  H —CF₃ H 4-8  methyl Cl methyl 4-9  H—OCH₃ H 4-10 methyl propyl methyl 4-11 H —S(O)₂CH₃ H 4-12 H —SCH(CH₃)₂ H4-13 —CF₃ H —CF₃ 4-14 CN H CN 4-15 H —NO₂ H 4-16 H pyridin-2-yl H 4-17 H—OH H 4-18 H

H 4-19 H —CH₂CH₂OH H 4-20 methyl —NHC(O)CH₃ methyl

The following Formula (1D1-1) compound names and example #'s refer tothose compounds depicted in Table 4. In one aspect of the invention, areFormula (1D1-1) compounds selected from the group consisting of:

-   (4-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1109);-   (4-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((4-bromo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1267);-   (4-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1361);-   (4-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(3-((4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (4-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1270);-   (4-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((4-ethyl-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1222);-   (4-7).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(3-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1245);-   (4-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1234);-   (4-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(3-((4-methoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1169);-   (4-10).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((3,5-dimethyl-4-propyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (4-11).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(3-((4-(methylsulfonyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1266);-   (4-12).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(3-((4-(isopropylthio)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1258);-   (4-13).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1381);-   (4-14).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(3,1-phenylene))bis(methylene))bis(1H-pyrazole-3,5-dicarbonitrile)    (1209);-   (4-15).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(3-((4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1199);-   (4-16).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(3-((4-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (4-17).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((4-hydroxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1141);-   (4-18).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(3,1-phenylene))bis(methylene))bis(N-cyclopropyl-1H-pyrazole-4-carboxamide)    (1276);-   (4-19).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(3-((4-(2-hydroxyethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197); and-   (4-20).    N,N′-((((((2R,5S,8S,11S,14R,17S,20S,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(3,1-phenylene))bis(methylene))bis(3,5-dimethyl-1H-pyrazole-1,4-diyl))diacetamide    (1280).

TABLE 4′ Formula (1D1-1) Table 4 Compound NMRs (1H NMR (400 Mhz,DMSO-d₆) δ ppm) Example NMR 4-1  0.67-0.97 (m, 24 H), 1.23-1.75 (m, 17H), 2.68-3.26 (m, 16 H), 4.37-4.48 (m, 1 H), 5.01-5.75 (m, 12 H),6.24-6.25 (m, 2 H), 7.05-7.44 (m, 10 H), 7.71-7.76 (m, 2 H) 4-2 0.65-0.94 (m, 24 H), 1.23-1.75 (m, 17 H), 2.67-3.04 (m, 16 H), 4.37-4.45(m, 1 H), 5.01-5.75 (m, 12 H), 7.05-7.30 (m, 8 H), 7.53-7.54 (m, 2 H),7.90-8.05 (m, 2 H) 4-3  0.65-0.97 (m, 24 H), 1.23-1.75 (m, 17 H),2.68-3.04 (m, 16 H), 4.37-4.45 (m, 1 H), 5.01-5.70 (m, 12 H), 7.17-7.29(m, 8 H), 7.51-7.53 (m, 2 H), 7.92-7.96 (m, 2 H) 4-4  0.87-0.97 (m, 28H), 1.23-1.69 (m, 20 H), 2.31-2.38 (m, 5 H), 2.68-3.26 (m, 16 H),4.41-4.48 (m, 1 H), 5.11-5.60 (m, 14 H), 7.11-7.13 (m, 4 H), 7.23-7.29(m, 6 H), 7.45-7.51 (m, 2 H) 4-5  0.44-0.54 (m, 8 H), 0.70-0.98 (m, 32H), 1.21-1.75 (m, 20 H), 2.67-3.05 (m, 15 H), 4.41-4.43 (m, 1 H),5.05-5.59 (m, 14 H), 6.73-6.87 (m, 2 H), 7.03-7.05 (m, 2 H), 7.21-7.27(m, 6 H) 4-6  0.72-1.00 (m, 26 H), 1.24-1.69 (m, 20 H), 2.04-2.10 (m, 12H), 2.27-2.32 (m, 5 H), 2.68-3.08 (m, 16 H), 4.41-4.43 (m, 1 H),5.12-5.36 (m, 12 H), 6.98-7.00 (m, 1 H), 7.18-7.20 (m, 2 H), 7.22-7.26(m, 5 H) 4-7  1H NMR (400 MHz, CDCl₃) δ: 0.80-0.93 (m, 20 H), 0.98-1.76(m, 20 H), 2.63- 3.11 (m, 18 H), 4.41-4.43 (m, 1 H), 5.28-5.61 (m, 11H), 7.20-7.71 (m, 12 H) 4-8  0.67-0.97 (m, 24 H), 1.23-1.71 (m, 17 H),2.03-2.18 (m, 12 H), 2.67-3.04 (m, 16 H), 4.39-4.42 (m, 1 H), 5.11-5.44(m, 12 H), 7.04-7.28 (m, 8 H) 4-9  0.69-0.97 (m, 24 H), 1.23-1.70 (m, 16H), 2.67-3.32 (m, 16 H), 3.62 (s, 6 H), 4.39-4.51 (m, 1 H), 4.95-5.69(m, 13 H), 6.98-7.49 (m, 12 H) 4-10 0.74-0.97 (m, 30 H), 1.23-1.69 (m,20 H), 2.02-2.08 (m, 12 H), 2.22-2.26 (m, 4 H), 2.67-3.25 (m, 16 H),4.41-4.48 (m, 1 H), 5.09-5.64 (m, 13 H), 6.71-6.79 (m, 1 H), 6.69-6.98(m, 2 H), 7.18-7.25 (m, 5 H) 4-11 0.71-0.97 (m, 24 H), 1.23-1.74 (m, 16H), 2.67-3.06 (m, 16 H), 3.18-3.19 (m, 6 H), 4.40-4.43 (m, 1 H),5.10-5.52 (m, 13 H), 7.25-7.34 (m, 8 H), 7.91-7.93 (m, 2 H), 8.45-8.51(m, 2 H) 4-12 0.74-0.94 (m, 24 H), 1.12-1.13 (m, 12 H), 1.23-1.66 (m, 18H), 2.67-3.03 (m, 16 H), 4.41-4.43 (m, 1 H), 5.11-5.67 (m, 13 H),7.08-7.29 (m, 8 H), 7.46 (s, 2 H), 7.85-7.9 (m, 2 H) 4-13 0.76-0.96 (m,24 H), 1.23-1.72 (m, 16 H), 2.66-3.05 (m, 16 H), 4.39-4.42 (m, 1 H),5.04-5.71 (m, 13 H), 6.72-6.82 (m, 1 H), 7.11-7.13 (m, 2 H), 7.25-7.37(m, 5 H), 7.63-7.69 (m, 2 H) 4-14 0.68-0.97 (m, 24 H), 1.23-1.73 (m, 17H), 2.66-3.25 (m, 16 H), 4.35-4.45 (m, 1 H), 5.01-5.81 (m, 12 H),7.03-7.42 (m, 8 H), 7.98-8.02 (m, 2 H) 4-15 0.67-0.96 (m, 24 H),1.23-1.57 (m, 17 H), 2.68-2.91 (m, 16 H), 4.47-4.53 (m, 1 H), 5.08-5.73(m, 12 H), 7.23-7.33 (m, 8 H), 8.26-8.28 (m, 2 H), 8.96-9.01 (m, 2 H)4-16 0.69-0.95 (m, 24 H), 1.25-1.81 (m, 17 H), 2.66-3.20 (m, 16 H),4.41-4.42 (m, 1 H), 5.03-5.70 (m, 12 H), 7.15-8.47 (m, 20 H) 4-170.67-0.97 (m, 24 H), 1.24-1.75 (m, 17 H), 2.68-3.04 (m, 16 H), 4.37-4.48(m, 1 H), 5.01-5.75 (m, 12 H), 6.98-7.27 (m, 12 H), 8.39-8.44 (m, 2 H)4-18 0.40-0.48 (m, 4 H), 0.60-1.00 (m, 28 H), 1.15-1.80 (m, 20 H),2.65-3.15 (m, 16 H), 4.35-4.42 (m, 1 H), 5.00-5.80 (m, 11 H), 7.15-7.40(m, 8 H), 7.80 (s, 2 H), 8.00-8.30 (m, 4 H) 4-19 0.65-1.00 (m, 24 H),1.15-1.80 (m, 18 H), 2.70-3.10 (m, 16 H), 3.45-3.55 (m, 4 H), 4.40-4.50(m, 2 H), 4.55-4.65 (m, 2 H), 5.05-5.80 (m, 14 H), 7.05-7.10 (m, 4 H),7.20-7.40 (m, 6 H), 7.50-7.60 (m, 2 H) 4-20 0.68-0.98 (m, 24 H),1.23-1.68 (m, 18 H), 1.95-2.01 (m, 18 H), 2.67-2.98 (m, 16 H), 4.40-4.50(m, 1 H), 5.00-5.80 (m, 11 H), 6.68-6.78 (m, 1 H), 6.98-7.05 (m, 2 H),7.15-7.40 (m, 5 H), 8.02-8.80 (m, 2 H)

The following Formula (1E1) compounds (meta hybrids) described in Table5 were prepared in accordance with the schemes and examples describedherein.

TABLE 5 Formula (1E1) Compounds # 3′ 4′ 5′ 5-1 H F H 5-2 H —NO₂ H 5-3 H—OH H 5-4 —CH₂OH H —CH₂OH 5-5 methyl —NHC(O)CH₃ methyl 5-6

H

The following Formula (1E1) compound names and example #'s refer tothose compounds depicted in Table 5. In one aspect of the invention, areFormula (1E1) compounds selected from the group consisting of:

-   (5-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(3-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1047);-   (5-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(3-((4-nitro-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1074);-   (5-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(3-((4-hydroxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1045);-   (5-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(3-((3,5-bis(hydroxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1089);-   (5-5).    N-(1-(3-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetamide    (1114); and-   (5-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(3-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1109).

TABLE 5′ Formula (1E1) Table 5 Coumpound NMRs (1H NMR (400 Mhz, DMSO-d₆)δ ppm) Example NMR 5-1 0.67-0.96 (m, 24 H), 1.23-1.62 (m, 17 H),2.69-3.09 (m, 16 H), 4.41-4.43 (m, 1 H), 5.06-5.70 (m, 10 H), 7.11-7.13(m, 1 H), 7.25-7.31 (m, 8 H), 7.47- 7.48 (m, 1 H), 7.93-7.94 (m, 1 H)5-2 0.64-0.96 (m, 24 H), 1.21-1.70 (m, 17 H), 2.67-3.07 (m, 16 H),4.37-4.48 (m, 1 H), 5.01-5.75 (m, 10 H), 7.22-7.42 (m, 9 H), 8.26-8.27(m, 1 H), 9.02- 9.03 (m, 1 H) 5-3 0.65-0.96 (m, 24 H), 1.23-1.71 (m, 17H), 2.67-3.08 (m, 16 H), 4.38-4.48 (m, 1 H), 5.01-5.75 (m, 10 H),6.99-7.31 (m, 11 H), 8.39-8.41 (m, 1 H) 5-4 0.65-1.00 (m, 24 H),1.05-1.75 (m, 18 H), 2.65-3.10 (m, 16 H), 4.33-4.42 (m, 4 H), 4.90-5.80(m, 12 H), 6.15 (s, 1H), 6.98-7.05 (m, 2 H), 7.15-7.40 (m, 7 H) 5-50.65-0.96 (m, 24 H), 1.15-1.70 (m, 17 H), 1.96-2.00 (m, 9 H), 2.69-3.06(m, 16 H), 4.40-4.45 (m, 1 H), 5.03-5.70 (m, 10 H), 6.92-7.05 (m, 2 H),7.18- 7.31 (m, 7 H), 8.95 (brs, 1 H) 5-6 0.46-0.54 (m, 4 H), 0.70-0.96(m, 28 H), 1.24-1.74 (m, 19 H), 2.68-3.06 (m, 16 H), 4.40-4.43 (m, 1 H),5.03-5.70 (m, 10 H), 6.92-7.31 (m, 10 H)

The following Formula (1A1-2) compounds (para/para; bis) described inTable 6 were prepared in accordance with the schemes and examplesdescribed herein.

TABLE 6 Formula (1A1-2) Symmetrical Compounds Ex 2 and 2′ 4 and 4′ 5 and5′ 6-1  methyl H H 6-2  H H H 6-3  Br H H 6-4  ethyl H H 6-5  methylmethyl H 6-6  t-butyl H H 6-7 

H H 6-8  isopropyl H H 6-9  Cl H H 6-10 I H H 6-11 phenyl H H 6-12 H BrH 6-13 H methyl methyl 6-14 H methyl H 6-15 —CF₃ H H 6-16 —CH₂OH H H6-17

H H 6-18

H H 6-19 —CH₂OCH₃ H H 6-20 —CH₂OCH₂CH₃ H HThe following Formula (1A1-2) compound names and example #'s refer tothose compounds depicted in Table 6. In one aspect of the invention, areFormula (1A1-2) compounds selected from the group consisting of:

-   (6-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-[(2-methylimidazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1138);-   (6-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-(imidazol-1-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1110);-   (6-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(2-bromoimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1268);-   (6-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(2-ethylimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1166);-   (6-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,4-dimethyl-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (6-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(2-tert-butylimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1222);-   (6-7).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(2-cyclopropylimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1190);-   (6-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((2-isopropyl-1H-imidazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (6-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-chloro-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1178);-   (6-10).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-iodo-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1361);-   (6-11).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-phenyl-1H-imidazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1262);-   (6-12).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-bromo-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1267);-   (6-13).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (6-14).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-methyl-1H-imidazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1137);-   (6-15).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1245);-   (6-16).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-(hydroxymethyl)-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1169);-   (6-17).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-(morpholinomethyl)-1H-imidazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1308);-   (6-18).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-(thiazol-5-yl)-1H-imidazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1276);-   (6-19).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((2-(methoxymethyl)-1H-imidazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1197); and-   (6-20).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-(ethoxymethyl)-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1226).

TABLE 6′ Formula (1A1-2) Table 6 Compound NMRs (1H NMR (400 MHz,DMSO-d₆) δ ppm) Example NMR 6-1  0.69-0.96 (m, 26H), 1.20-1.76 (m, 16H), 2.57 (s, 6H), 2.65-3.12 (m, 16 H), 4.38- 5.74 (m, 12H), 7.28-7.31(m, 4H), 7.34-7.39 (m, 4 H), 7.60 (d, 2 H), 7.64-7.67 (m, 2H) 6-2 0.65-0.98 (m, 26H), 1.15-1.74 (m, 16 H), 2.66-3.11 (m, 16 H), 4.38-5.75(m, 12 H), 7.34-7.42 (m, 8 H), 7.72 (d, 4 H), 9.25 (s, 2H) 6-3 0.68-0.95 (m, 26H), 1.20-1.74 (m, 16 H), 2.67-3.09 (m, 16 H), 4.38-5.73(m, 12 H), 7.03-7.05 (m, 2 H), 7.14 (d, 4 H), 7.32 (dd, 4 H), 7.45-7.47(m, 2H) 6-4  0.68-0.95 (m, 26H), 1.14-1.75 (m, 22 H), 2.67-3.11 (m, 20H), 4.38-5.73 (m, 12 H), 7.26-7.31 (m, 4 H), 7.37 (d, 4 H), 7.64-7.71(m, 4H) 6-5  0.69-0.94 (m, 26H), 1.21-1.76 (m, 16 H), 2.20 (s, 6 H),2.54 (s, 6 H), 2.67-3.11 (m, 16 H), 4.39-5.73 (m, 12 H), 7.27-7.39 (m,10 H) 6-6  0.69-0.95 (m, 26H), 1.24-1.77 (m, 34 H), 2.66-3.10 (m, 16 H),4.39-5.69 (m, 12 H), 7.09-7.14 (m, 4 H), 7.37 (d, 4 H), 7.54-7.56 (m,2H), 7.66-7.68 (m, 2 H) 6-7  0.69-0.94 (m, 26H), 1.04-1.75 (m, 24 H),2.31-2.38 (m, 2 H), 2.67-3.11 (m, 16 H), 4.39-5.74 (m, 12 H), 7.30-7.38(m, 8 H), 7.57 (d, 2 H), 7.69 (d, 2H) 6-8  0.70-0.94 (m, 26H), 1.16-1.77(m, 28 H), 2.66-3.11 (m, 16 H), 3.46-3.54 (m, 2 H), 4.39-5.71 (m, 12 H),7.26-7.38 (m, 8 H), 7.69-7.73 (m, 4 H) 6-9  0.69-0.95 (m, 26H),1.19-1.74 (m, 16 H), 2.67-3.09 (m, 16 H), 4.39-5.72 (m, 12 H), 6.92-6.94(m, 2 H), 7.15 (d, 4 H), 7.30-7.39 (m, 6 H) 6-10 0.69-0.96 (m, 26H),1.20-1.75 (m, 16 H), 2.67-3.11 (m, 16 H), 4.39-5.73 (m, 12 H), 7.17-7.21(m, 4 H), 7.32-7.37 (m, 4 H), 7.46-7.50 (m, 2 H), 7.71-7.75 (m, 2 H)6-11 0.64-0.92 (m, 26H), 1.19-1.75 (m, 16 H), 2.67-3.07 (m, 16 H),4.38-5.69 (m, 12 H), 7.06 (d, 4 H), 7.27-7.31 (m, 4 H), 7.60-7.73 (m, 10H), 7.83-7.89 (m, 4 H) 6-12 0.69-0.96 (m, 26H), 1.20-1.76 (m, 16 H),2.67-3.10 (m, 16 H), 4.39-5.72 (m, 12 H), 7.18-7.21 (m, 4 H), 7.32-7.37(m, 4 H), 7.48-7.62 (m, 2 H), 8.67-8.79 (m, 2 H) 6-13 0.69-0.96 (m,26H), 1.19-1.75 (m, 16 H), 2.06 (s, 6 H), 2.19 (s, 6 H), 2.67-3.11 (m,16 H), 4.39-5.73 (m, 12 H), 7.22-7.26 (m, 4 H), 7.34-7.39 (m, 4 H), 9.09(s, 2 H) 6-14 0.67-0.95 (m, 26H), 1.20-1.75 (m, 16 H), 2.23 (s, 6 H),2.67-3.11 (m, 16 H), 4.39- 5.75 (m, 12 H), 7.24-7.47 (m, 10 H),9.11-9.13 (m, 2 H) 6-15 0.69-0.94 (m, 26H), 1.20-1.76 (m, 16 H),2.66-3.09 (m, 16 H), 4.38-5.71 (m, 12 H), 7.09-7.15 (m, 6 H), 7.29-7.34(m, 4 H), 7.57-7.59 (m, 2H) 6-16 0.69-0.94 (m, 26H), 1.20-1.75 (m, 16H), 2.67-3.11 (m, 16 H), 4.39-5.74 (m, 16 H), 7.31-7.38 (m, 8 H),7.63-7.67 (m, 4 H) 6-19 0.69-0.95 (m, 26H), 1.20-1.76 (m, 16 H),2.67-3.12 (m, 16 H), 3.33 (s, 6 H), 4.40- 5.74 (m, 16 H), 7.31-7.38 (m,8 H), 7.68-7.74 (m, 4 H) 6-20 0.69-0.94 (m, 26H), 1.09-1.14 (m, 6 H),1.20-1.76 (m, 16 H), 2.67-3.12 (m, 16 H), 3.50-3.56 (m, 4 H), 4.39-5.74(m, 16 H), 7.32-7.38 (m, 8 H), 7.68-7.74 (m, 4 H)

The following Formula (1C1-2) compounds (meta/para) described in Table 7were prepared in accordance with the schemes and examples describedherein.

TABLE 7 Formula (1C1-2) Compounds # 2 and 2′ 4 and 4′ 5 and 5′ 7-1methyl H H 7-2 H H H 7-3 Br H H 7-4 ethyl H H 7-5 methyl methyl H 7-6t-butyl H H 7-7

H H 7-8 isopropyl H H 7-9 Cl H H  7-10 I H H  7-11 —CH₂OH H H

The following Formula (1C1-2) compound names and example #'s refer tothose compounds depicted in Table 7. In one aspect of the invention, areFormula (1C1-2) compounds selected from the group consisting of:

-   (7-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-[[3-[(2-methylimidazol-111)methyl]phenyl]methyl]-24-[[4-[(2-methylimidazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1138);-   (7-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((1H-imidazol-1-yl)methyl)benzyl)-18-(4-((1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1109);-   (7-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[3-[(2-bromoimidazol-1-yl)methyl]phenyl]methyl]-18-[[4-[(2-bromoimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1268);-   (7-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[3-[(2-ethylimidazol-1-yl)methyl]phenyl]methyl]-18-[[4-[(2-ethylimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1166);-   (7-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((2,4-dimethyl-1H-imidazol-1-yl)methyl)benzyl)-18-(4-((2,4-dimethyl-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1165);-   (7-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)benzyl)-18-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1222);-   (7-7).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-[[3-[(2-cyclopropylimidazol-1-yl)methyl]phenyl]methyl]-18-[[4-[(2-cyclopropylimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1190);-   (7-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(3-((2-isopropyl-1H-imidazol-1-yl)methyl)benzyl)-18-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1194);-   (7-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((2-chloro-1H-imidazol-1-yl)methyl)benzyl)-18-(4-((2-chloro-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1178);-   (7-10).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((2-iodo-1H-imidazol-1-yl)methyl)benzyl)-18-(4-((2-iodo-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1361); and-   (7-11).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(3-((2-(hydroxymethyl)-1H-imidazol-1-yl)methyl)benzyl)-18-(4-((2-(hydroxymethyl)-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1169).

TABLE 7′ Formula (1C1-2) Table 7 Compound NMRs (1H NMR (400 Mhz,DMSO-d₆) δ ppm) Example NMR 7-1 0.64-0.96 (m, 26H), 1.21-1.76 (m, 16 H),2.56-2.62 (m, 6H) 2.64-3.10 (m, 16 H), 4.39-5.77 (m, 12 H), 7.23-7.44(m, 8H), 7.57-7.67 (m, 4 H) 7-2 0.63-0.94 (m, 26H), 1.19-1.76 (m, 16 H),2.68-3.16 (m, 16 H), 4.39-5.77 (m, 12 H), 7.30-7.52 (m, 8 H), 7.68-7.78(m, 4 H), 9.25 (s, 2 H) 7-3 0.64-0.95 (m, 26 H), 1.17-1.77 (m, 16 H),2.67-3.10 (m, 16 H), 4.39-5.75 (m, 12 H), 7.04-7.35 (m, 10 H), 7.46-7.49(m, 2 H) 7-4 0.65-0.95 (m, 26 H), 1.14-1.77 (m, 22 H), 2.67-3.14 (m, 20H), 4.39-5.76 (m, 12 H), 7.20-7.43 (m, 8 H), 7.63-7.71 (m, 4 H) 7-50.65-0.94 (m, 26 H), 1.22-1.77 (m, 16 H), 2.20 (s, 6 H), 2.58 (s, 6 H),2.68-3.12 (m, 16 H), 4.39-5.79 (m, 12 H), 7.21-7.43 (m, 10 H) 7-60.70-0.95 (m, 26 H), 1.23-1.78 (m, 34 H), 2.67-3.11 (m, 16 H), 4.39-5.73(m, 12 H), 7.10-7.13 (m, 2H), 7.28-7.39 (m, 6H), 7.49-7.56 (m, 2 H),7.66-7.70 (m, 2 H) 7-7 0.66-0.94 (m, 26 H), 1.04-1.76 (m, 24 H),2.31-2.38 (m, 2 H), 2.68-3.14 (m, 16 H), 4.39-5.78 (m, 12H), 7.22-7.47(m, 8H), 7.55-7.57 (m, 2 H), 7.69-7.71 (m, 2 H) 7-8 0.67-0.94 (m, 26 H),1.16-1.78 (m, 28 H), 2.67-3.12 (m, 16 H), 3.46-3.56 (m, 2 H), 4.39-5.75(m, 12 H), 7.16-7.45 (m, 8 H), 7.68-7.73 (m, 4 H) 7-9 0.66-0.94 (m, 26H), 1.20-1.75 (m, 16 H), 2.68-3.11 (m, 16 H), 4.39-5.75 (m, 12 H),6.93-6.95 (m, 2 H), 7.05-7.34 (m, 8 H), 7.39-7.41 (m, 2 H)  7-100.67-0.95 (m, 26 H), 1.18-1.76 (m, 16 H), 2.68-3.13 (m, 16 H), 4.39-5.75(m, 12 H), 7.09-7.50 (m, 10 H), 7.68-7.73 (m, 2 H)  7-11 0.65-0.95 (m,26 H), 1.18-1.76 (m, 16 H), 2.68-3.13 (m, 16 H), 4.39-5.76 (m, 16 H),7.25-7.47 (m, 8 H), 7.62-7.70 (m, 4 H)

The following Formula (1B1-2) compounds (hybrid analogs) described inTable 8 were prepared in accordance with the schemes and examplesdescribed herein.

TABLE 8 Formula (1B1-2) Compounds # 2′ 4′ 5′ 8-1 methyl H H 8-2 H H H8-3 Br H H 8-4 ethyl H H 8-5 methyl methyl H 8-6 t-butyl H H 8-7

H H 8-8 isopropyl H H 8-9 Cl H H  8-10 I H H  8-11 H methyl methyl  8-12—CF₃ H H  8-13 —CH₂OH H H  8-14 —CH₂F H H  8-15 H Br H

The following Formula (1B1-2) compound names and example #'s refer tothose compounds depicted in Table 8. In one aspect of the invention, areFormula (1B1-2) compounds selected from the group consisting of:

-   (8-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-[[4-[(2-methylimidazol-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1043);-   (8-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-(imidazol-1-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1029);-   (8-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[(2-bromoimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1108);-   (8-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[(2-ethylimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1058);-   (8-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((2,4-dimethyl-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1057);-   (8-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[(2-tert-butylimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1086);-   (8-7).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-[(2-cyclopropylimidazol-1-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1069);-   (8-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-18-(4-((2-isopropyl-1H-imidazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1071);-   (8-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((2-chloro-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1064);-   (8-10).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((2-iodo-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1155);-   (8-11).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1057);-   (8-12).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1097);-   (8-13).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((2-(hydroxymethyl)-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1059);-   (8-14).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((2-(fluoromethyl)-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1061); and-   (8-15).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-bromo-1H-imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1108).

TABLE 8′ Formula (1B1-2) Table 8 Compound NMRs (1H NMR (400 Mhz,DMSO-d₆) δ ppm) Example NMR 8-1 0.69-0.96 (m, 26H), 1.20-1.76 (m, 16 H),2.57 (s, 3H), 2.65-3.11 (m, 16 H), 4.38- 5.76 (m, 10 H), 7.22-7.38 (m,9H), 7.59-7.66 (m, 2H) 8-2 0.65-0.96 (m, 26H), 1.17-1.77 (m, 16 H),2.66-3.12 (m, 16 H), 4.38-5.75 (m, 10 H), 7.22-7.41 (m, 9H), 7.72 (d,2H), 9.25 (s, 1H) 8-3 0.69-0.98 (m, 26H), 1.20-1.77 (m, 16 H), 2.66-3.12(m, 16 H), 4.39-5.75 (m, 10 H), 7.02 (s, 1 H), 7.14 (d, 2 H), 7.23-7.35(m, 7H), 7.45-7.47 (m, 1H) 8-4 0.66-0.96 (m, 26H), 1.14-1.76 (m, 19 H),2.67-3.11 (m, 18 H), 4.39-5.75 (m, 10 H), 7.22-7.39 (m, 9H), 7.65-7.71(m, 2H) 8-5 0.69-0.96 (m, 26 H), 1.20-1.76 (m, 16 H), 2.20 (s, 3 H),2.54 (s, 3 H), 2.68-3.11 (m, 16 H), 4.38-5.75 (m, 10 H), 7.22-7.39 (m,10 H) 8-6 0.67-0.96 (m, 26 H), 1.21-1.77 (m, 25 H), 2.66-3.11 (m, 16 H),4.39-5.75 (m, 10 H), 7.10-7.39 (m, 9 H), 7.54-7.56 (m, 1 H), 7.67-7.68(m, 1 H) 8-7 0.68-0.96 (m, 26H), 1.04-1.77 (m, 20 H), 2.31-2.38 (m, 1H), 2.67-3.11 (m, 16 H), 4.39-5.75 (m, 10 H), 7.22-7.38 (m, 9H), 7.57(d, 1 H), 7.69 (d, 1 H) 8-8 0.69-0.96 (m, 26 H), 1.16-1.77 (m, 22 H),2.66-3.11 (m, 16 H), 3.47-3.55 (m, 1 H), 4.39-5.75 (m, 10 H), 7.22-7.39(m, 9H), 7.70-7.73 (m, 2 H) 8-9 0.69-0.96 (m, 26 H), 1.20-1.76 (m, 16H), 2.67-3.11 (m, 16 H), 4.39-5.75 (m, 10 H), 6.92 (s, 1 H), 7.14-7.39(m, 10 H)  8-10 0.69-0.96 (m, 26 H), 1.20-1.76 (m, 16 H), 2.67-3.11 (m,16 H), 4.39-5.75 (m, 10 H), 7.15-7.49 (m, 10 H), 7.71-7.75 (m, 1 H) 8-11 0.69-0.96 (m, 26 H), 1.20-1.76 (m, 16 H), 2.06 (s, 3 H), 2.18 (s,3 H), 2.66-3.12 (m, 16 H), 4.38-5.75 (m, 10 H), 7.22-7.38 (m, 9 H), 9.09(s, 1 H)  8-12 0.69-0.96 (m, 26 H), 1.20-1.76 (m, 16 H), 2.67-3.10 (m,16 H), 4.39-5.75 (m, 10 H), 7.10-7.16 (m, 3 H), 7.23-7.35 (m, 7 H),7.58-7.60 (m, 1 H)  8-13 0.69-0.96 (m, 26 H), 1.19-1.76 (m, 16 H),2.68-3.12 (m, 16 H), 4.40-5.75 (m, 12 H), 7.22-7.38 (m, 9 H), 7.64-7.67(m, 2 H)  8-14 0.69-0.96 (m, 26 H), 1.19-1.75 (m, 16 H), 2.67-3.11 (m,16 H), 4.38-5.79 (m, 12 H), 7.23-7.38 (m, 9 H), 7.62 (s, 1 H), 7.72 (s,1 H)  8-15 0.68-0.96 (m, 26 H), 1.19-1.79 (m, 16 H), 2.67-3.13 (m, 16H), 4.39-5.75 (m, 10 H), 7.17-7.36 (m, 9 H), 7.43-7.55 (m, 1 H),8.55-8.73 (m, 1 H)

The following Formula (1F1) compounds (para/para; bis) described inTable 9 were prepared in accordance with the schemes and examplesdescribed herein. Rings A and B are as described herein.

TABLE 9 Formula (1F1) Symmetrical Compounds Ex.# Ring A/Ring B 9-1 

9-2 

9-3 

9-4 

9-5 

9-6 

9-7 

9-8 

9-9 

9-10

9-11

9-12

9-13

9-14

9-15 No example 9-16

9-17

9-18

9-19

9-20

9-21

9-22

9-23

9-24

9-25

9-26

9-27

9-28

9-29

9-30

9-31

9-32

9-33

9-34

9-35

9-36

9-37

9-38

9-39

9-40

9-41

9-42

9-43

9-44 No example 9-45

9-46

9-47

9-48

9-49

9-50

9-51

9-52

9-53

9-54

9-55

9-56

9-57

9-58

9-59

9-60

9-61

9-62

9-63

9-64

9-65

9-66

9-67

9-68

9-69

The following Formula (1F1) compound names and example #'s refer tothose compounds depicted in Table 9. In one aspect of the invention areFormula (1F1) compounds selected from:

-   (9-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(morpholinomethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1148);-   (9-2).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(thiomorpholinomethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1180);-   (9-3).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(piperidin-1-ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1144);-   (9-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4,4-difluoropiperidin-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1215);-   (9-5)    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-(3,3-difluoropiperidin-1-yl)benzyl)-18-(4-((3,3-difluoropiperidin-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1215);-   (9-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1H-1,2,3-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1111);-   (9-7).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(piperidine-4-carbonitrile)    (1194);-   (9-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-methoxypiperidin-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1204);-   (9-9).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-hydroxy-4-methylpiperidin-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1204);-   (9-10).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-(methoxymethyl)piperidin-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1232);-   (9-11)    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,5-dioxopyrrolidin-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1171);-   (9-12).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrrole-2,5-dicarbonitrile)    (1207);-   (9-13).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-(1,2,4-triazol-1-ylmethyl)phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1112);-   (9-14).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-tosyl-1H-tetrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1422);-   (9-15). No example;-   (9-16).    1-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-[[4-[(2-cyanopyrrol-1-yl)methyl]phenyl]methyl]-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrrole-2-carbonitrile    (1157);-   (9-17).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[[(3-methyl-2,5-dioxo-imidazolidin-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1201);-   (9-18).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1H-tetrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1113);-   (9-19). diethyl    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-tetrazole-5-carboxylate)    (1257);-   (9-20).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-bromo-2-oxopyridin-1(2H)-    yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1321);-   (9-21).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-chloro-2-oxopyridin-1(2H)-    yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1232);-   (9-22).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1299);-   (9-23).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1209);-   (9-24).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1209);-   (9-25).    1-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-[[4-[(3-cyanopyrrol-1-yl)methyl]phenyl]methyl]-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrrole-3-carbonitrile    (1057);-   (9-26).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1244);-   (9-27).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-methyl-2-oxopyridin-1(2H)-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1191);-   (9-28).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1163);-   (9-29).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1211);-   (9-30).    N′-hydroxy-1-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-[[4-[[2-[(Z)—N′-hydroxycarbamimidoyl]pyrrol-1-yl]methyl]phenyl]methyl]-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrrole-2-carboxamidine    (1223);-   (9-31).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-oxooxazolidin-3-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1147);-   (9-32).    1-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-[[4-[(2-carbamoylpyrrol-1-yl)methyl]phenyl]methyl]-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrrole-2-carboxamide    (1215);-   (9-33).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1106);-   (9-34).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-phenyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1264);-   (9-35).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2H-indazol-2-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1209);-   (9-36). di-tert-butyl    2,2′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate)    (1392);-   (9-37).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-(hydroxymethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1250);-   (9-38).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile)    (1240);-   (9-39).    2-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-(4-((3-cyano-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)methyl)benzyl)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile    (1240);-   (9-40).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1191);-   (9-41).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((6,7-dihydropyrano[4,3-c]pyrazol-2(4H)-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1221);-   (9-42)    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-(5,6-dihydro-4H-cyclopenta[c]pyrazol-2-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1188);-   (9-43).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[(5-acetyl-4,6-dihydropyrrolo[3,4-c]pyrazol-2-yl)methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1276);-   (9-44). No example.-   (9-45).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1H-benzo[d]imidazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1209);-   (9-46).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(pyrrolidin-1-ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1115);-   (9-47).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1220);-   (9-48).    1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(5-methyl-1H-pyrrole-2-carbonitrile)    (1185);-   (9-49).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1211);-   (9-50).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-ethyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1167);-   (9-51).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(tert-butyl)-1H-1,2,4-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1224);-   (9-52).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclopentyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1248);-   (9-53).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-isobutyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1224);-   (9-54).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclobutyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1220);-   (9-55).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(cyclopropylmethyl)-1H-1,2,4-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1220);-   (9-56).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-neopentyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1252);-   (9-57).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclopropyl-3-methyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1220);-   (9-58).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(4-chlorophenyl)-1H-1,2,4-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1332);-   (9-59).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-ethyl-3-methyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1196);-   (9-60).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-(2,3-dihydropyrido[2,3-b][1,4]oxazin-1-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1244);-   (9-61).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-[(3-oxopyrido[3,2-b][1,4]thiazin-4-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1306);-   (9-62).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1,1-dioxido-2,3-dihydro-4H-pyrido[3,2-b][1,4]thiazin-4-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1338);-   (9-63).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-(2,3-dihydropyrido[4,3-b][1,4]oxazin-4-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1246);-   (9-64).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-(2,3-dihydropyrido[3,2-b][1,4]oxazin-4-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1244);-   (9-65).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-(2,3-dihydropyrido[2,3-b][1,4]thiazin-1-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1276);-   (9-66).    (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-[(4-methyl-2,3-dihydroquinoxalin-1-yl)methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1269);-   (9-67). tert-butyl    4-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-[[4-[(4-tert-    butoxycarbonyl-2,3-dihydroquinoxalin-1-yl)methyl]phenyl]methyl]-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]-2,3-dihydroquinoxaline-1-carboxylate    (1440);-   (9-68).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1276); and-   (9-69).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    dihydrochloride (1240).

TABLE 9′ Formula (1F1) Table 9 Compound NMRs (1H NMR (400 Mhz, DMSO-d₆)δ ppm) Example NMR 9-1  0.67-0.94 (m, 26H), 1.16-1.76 (m, 16H),2.37-3.22 (m, 24H), 3.46-3.60 (m, 4H), 3.65-3.82 (m, 8H), 4.44-5.75 (m,8 H), 7.14-7.37 (m, 8H) 9-2  1H NMR (400 MHz, CDCl3) δ 0.78-1.10 (m,30H), 1.20-1.78 (m, 12H), 2.55-3.20 (m, 32H), 3.46 (s, 4H), 4.40-4.50(m, 1H), 5.00-5.78 (m, 7H), 7.10-7.40 (m, 8H) 9-6  0.6-1.0 (m, 29H),1.1-1.8 (m, 17 H), 2.6-3.1 (m, 17 H), 4.35-4.45 (m, 0.5H), 5.0- 5.75 (m,12 H), 7.2-7.35 (8H), 7.73 (s, 2H), 8.14 (s, 2H). 9-11 0.6-1.0 (m, 28H),1.1-1.8 (m, 16 H), 2.65-3.15 (m, 24 H), 4.3-4.5 (m, 1H), 4.51 (s, 4H),4.4-4.45 (m, 0.6H), 5.0-5.8 (m, 7.4 H), 7.15-7.30 (m, 8H). 9-120.69-0.96 (m, 28 H), 1.23-1.71 (m, 14 H), 2.66-3.09 (m, 16 H), 4.40-4.45(m, 1 H), 5.09-5.71 (m, 11 H), 7.05-7.11 (m, 4 H), 7.21 (s, 4 H),7.36-7.39 (m, 4 H) 9-13 0.64-0.94 (m, 26H), 1.18-1.76 (m, 16 H),2.67-3.07 (m, 16 H), 4.39-5.73 (m, 12 H), 7.28-7.37 (m, 8H), 8.78-8.82(m, 4H) 9-14 0.6-1.0 (m, 28H), 1.1-1.8 (m, 14 H), 2.44 (s, 6H), 2.6-3.0(m, 13 H), 3.0-3.1 (m, 3H), 4.3-4.5 (m, 0.7H), 5.0-5.8 (m, 8 H), 5.96(s, 4H), 7.23 (d, 4H), 7.35 (d, 4H), 7.52 (d, 4H), 7.90 (d, 4H). 9-160.67-1.04 (m, 26 H), 1.16-1.80 (m, 16 H), 2.62-2.96 (m, 13 H), 2.99-3.13(m, 3 H), 4.32-4.49 (m, 1 H), 4.96-5.75 (m, 11 H), 6.16-6.28 (m, 2 H),6.88-7.00 (m, 2 H), 7.05-7.18 (m, 4 H), 7.24-7.42 (m, 6 H) 9-170.65-0.98 (m, 26 H) 1.14-1.78 (m, 16 H) 2.63-2.95 (m, 19 H) 2.99-3.10(m, 3 H) 3.98-4.04 (m, 4H) 4.39-4.47 (m, 1H) 4.50 (s, 4H) 4.99-5.77 (m,7H) 7.14- 7.34 (m, 8H) 9-18 0.6-1.0 (m, 28H), 1.1-1.8 (m, 14 H), 2.6-3.1(m, 16H), 4.3-4.5 (m, 0.6H), 5.0-5.8 (m, 11.4 H), 7.25-7.40 (m, 8H).9-19 0.6-1.0 (m, 30H), 1.1-1.8 (m, 18 H), 2.6-3.1 (m, 16H), 4.3-4.5 (m,4.5H), 4.95-6.0 (m, 12.6 H), 7.25-7.40 (m, 8H). 9-20 0.61-0.99 (m, 26 H)1.13-1.75 (m, 16 H) 2.64-3.11 (m, 16 H) 4.37-4.46 (m, 1 H) 4.98-5.76 (m,11 H) 6.47 (br d, J = 7.34 Hz, 2 H) 6.69-6.78 (m, 2 H) 7.21- 7.33 (m, 8H) 7.73-7.81 (m, 2 H) 9-21 0.63-0.99 (m, 26 H) 1.13-1.75 (m, 16 H)2.64-3.10 (m, 16 H) 4.36-4.48 (m, 1 H) 4.96-5.76 (m, 11 H) 6.38 (br d, J= 7.34 Hz, 2 H) 6.52-6.60 (m, 2 H) 7.23- 7.35 (m, 8 H) 7.82-7.92 (m, 2H) 9-22 0.57-1.00 (m, 26 H) 1.10-1.80 (m, 16 H) 2.61-3.13 (m, 16 H)4.32-4.49 (m, 1 H) 4.98-5.78 (m, 11 H) 6.51-6.62 (m, 2 H) 7.24-7.37 (m,8 H) 7.62-7.74 (m, 2 H) 8.45-8.55 (m, 2 H) 9-23 0.50-1.04 (m, 27 H)1.05-1.82 (m, 15 H) 2.57-3.10 (m, 16 H) 4.29-4.45 (m, 1 H) 4.90-5.74 (m,7 H) 5.84-6.09 (m, 4 H) 6.87-7.07 (m, 2 H) 7.30-7.52 (m, 8 H) 7.57-7.79(m, 2 H) 7.92-8.07 (m, 2 H) 8.62-8.88 (m, 4 H) 13.52-13.68 (m, 2 H) 9-240.55-1.02 (m, 27 H) 1.05-1.77 (m, 15 H) 2.57-3.12 (m, 16 H) 4.35-4.49(m, 1 H) 4.94-5.59 (m, 6 H) 5.62-5.74 (m, 1 H) 5.74-5.87 (m, 4 H)6.85-7.04 (m, 2 H) 7.27-7.44 (m, 4 H) 7.44-7.54 (m, 4 H) 8.02-8.22 (m, 2H) 8.27-8.39 (m, 2 H) 8.39-8.57 (m, 2 H) 9.38-9.52 (m, 2 H) 12.97-13.13(m, 2 H) 9-25 0.64-0.99 (m, 26 H) 1.14-1.76 (m, 16 H) 2.63-2.95 (m, 13H) 2.96-3.13 (m, 3 H) 4.41 (m, 1 H) 4.98-5.76 (m, 11 H) 6.41-6.54 (m, 2H) 6.92-7.05 (m, 2 H) 7.17-7.38 (m, 8 H) 7.60-7.73 (m, 2 H) 9-260.67-1.01 (m, 27 H), 1.17-1.76 (m, 15 H), 2.63-3.09 (m, 16 H), 3.30-3.33(m, 4 H), 4.16-4.23 (m, 4 H), 4.30-4.45 (m, 5 H), 4.94-5.74 (m, 7 H),6.45-6.55 (m, 2 H), 6.55-6.72 (m, 6 H), 7.19-7.32 (m, 8 H) 9-270.62-0.99 (m, 26 H) 1.13-1.78 (m, 16 H) 2.04-2.15 (m, 6 H) 2.64-3.11 (m,16 H) 4.35-4.49 (m, 1 H) 4.96-5.75 (m, 11 H) 6.04-6.11 (m, 2 H) 6.21 (s,2 H) 7.19-7.31 (m, 8 H) 7.56-7.63 (m, 2 H) 9-28 0.6-1.0 (m, 32H),1.1-1.8 (m, 20 H), 2.6-3.1 (m, 16 H), 4.3-4.5 (m, 1H), 5.0-5.75 (m, 13H), 6.15-6.25 (m, 2H), 6.38 (d, 2H), 7.2-7.3 (8H), 7.35-7.45 (m, 2H),7.7- 7.75 (m, 2H). 9-29 0.6-1.0 (m, 33H), 1.1-1.8 (m, 25 H), 2.6-3.1 (m,16 H), 4.3-4.6 (m, 0.6H), 4.95- 5.75 (m, 6.8 H), 5.94 (s, 4H), 7.28 (s,8H), 7.35-7.45 (m, 2H), 7.45-7.55 (m, 2H), 7.79 (d, 2H), 8.03 (d, 2H).9-30 0.64-0.99 (m, 26 H), 1.16-1.79 (m, 16 H), 2.65-3.17 (m, 16 H),4.34-4.51 (m, 1 H), 4.93-5.74 (m, 11 H), 6.18-6.34 (m, 2 H), 6.61-6.79(m, 2 H), 6.91-7.42 (m, 10 H) 9-31 0.62-1.03 (m, 26 H) 1.06-1.92 (m, 20H) 2.60-3.00 (m, 16 H) 3.38 (m 4 H) 4.14- 4.37 (m, 4 H) 4.91-5.90 (m, 8H) 7.10-7.51 (m, 8 H) 9-32 0.62-0.96 (m, 26 H), 1.15-1.78 (m, 16 H),2.64-2.92 (m, 13 H), 2.96-3.08 (m, 3 H), 4.34-4.50 (m, 1 H), 4.95-5.75(m, 11 H), 5.98-6.11 (m, 2 H), 6.68-7.12 (m, 8 H), 7.21 (m, 4 H),7.33-7.57 (m, 2 H) 9-33 0.62-0.99 (m, 26 H) 1.06-1.81 (m, 16 H)2.61-3.14 (m, 16 H) 4.36-4.49 (m, 1 H) 4.97-5.78 (m, 9 H) 7.20-7.37 (m,10 H) 7.39-7.48 (m, 2 H) 7.78-7.88 (m, 2 H) 8.57-8.63 (m, 1 H) 9-340.68-0.96 (m, 26 H), 1.18-1.76 (m, 16 H), 2.67-3.08 (m, 16 H), 4.40-5.71(m, 12 H), 7.02 (d, 4 H), 7.28-7.32 (m, 4 H), 7.48-7.56 (m 6 H),7.62-7.65 (m 4 H), 8.11- 8.13 (m, 2 H) 9-35 0.66-0.96 (m, 26 H),1.20-1.76 (m, 16 H), 2.62-3.07 (m, 16 H), 4.40-5.71 (m, 12 H), 7.02 (d,4 H), 7.28-7.32 (m, 4 H), 7.48-7.56 (m 6 H), 7.62-7.65 (m 4 H), 8.11-8.13 (m, 2 H) 9-36 0.71-0.93 (m, 24 H), 1.17-1.67 (m, 33 H), 2.67-3.04(m, 16 H), 4.12-4.42 (m, 9 H), 5.03-5.68 (m, 14 H), 7.16-7.19 (m, 4 H),7.25-7.31 (m, 6 H) 9-37 0.71-0.98 (m, 24 H), 1.22-1.33 (m, 6 H),1.36-1.51 (m, 3 H), 1.52-1.78 (m, 4 H), 2.43 (br d, 4 H), 2.49-2.54 (m,8 H), 2.70 (s, 2 H), 2.78 (d, 4 H), 2.86-2.97 (m, 6 H), 3.05 (br s, 3H), 4.33 (s, 4 H), 4.40-4.53 (m, 1 H), 4.94 (br s, 1 H), 4.99- 5.09 (m,1 H), 5.10-5.30 (m, 8 H), 5.30-5.58 (m, 6 H), 5.60-5.87 (m, 3 H), 7.16(d, 4 H), 7.30 (br d, 4 H) 9-39 0.62-0.96 (m, 26 H), 1.08-1.75 (m, 16H), 2.20-3.04 (m, 30 H), 4.34-4.44 (m, 1 H), 4.97-5.15 (m, 3 H),5.17-5.44 (m, 5 H), 5.45-5.57 (m, 1 H), 5.61-5.73 (m, 1 H), 7.02-7.43(m, 1 H), 7.11-7.33 (m, 6 H) 9-40 0.72-0.94 (m, 24 H), 1.18-1.72 (m, 18H), 2.68-3.05 (m, 16 H), 4.14-4.20 (m, 8 H), 4.41-4.44 (m, 1 H),4.98-5.74 (m, 11 H), 7.22-7.32 (m, 10H), 10.11 (brs, 4 H) 9-41 0.53-1.07(m, 26 H) 1.04-1.89 (m, 16 H) 2.54-3.15 (m, 20 H) 4.41 (m, 1 H) 4.54 (m,4 H) 4.90-5.83 (m, 12 H) 6.82-7.40 (m, 8 H) 7.47 (m, 2 H) 9-42 0.68-0.94(m, 26 H), 1.20-1.77 (m, 18 H), 2.26-2.43 (m, 6 H), 2.67-3.03 (m, 18 H),4.40-4.42 (m, 1 H), 5.01-5.71 (m, 13 H), 7.09-7.34 (m, 10 H) 9-430.68-0.94 (m, 27 H), 1.20-1.70 (m, 15 H), 1.97 (s, 6 H), 2.67-3.04 (m,16 H), 4.17-4.31 (m, 4 H), 4.33-4.44 (m, 1 H), 4.47-4.55 (m, 4 H),5.02-5.69 (m, 11 H), 7.16-7.19 (m, 4 H), 7.26-7.30 (m, 6 H) 9-45 0.6-1.0(m, 28H), 1.1-1.8 (m, 15 H), 2.6-3.1 (m, 16 H), 4.3-4.5 (m, 0.6H), 4.95-5.75 (m, 11 H), 7.15-7.3 (12H), 7.4-7.5 (m, 2H), 7.6-7.7 (m, 2H). 9-460.6-1.0 (m, 29H), 1.1-1.8 (m, 26 H), 2.35-2.45 (m, 8H), 2.6-3.1 (m, 20H), 4.4-4.5 (m, 1H), 4.95-5.75 (m, 8 H), 7.2-7.3 (8H), 8.26 (s, 2H).9-47 0.74-0.94 (m, 28 H), 1.27-1.90 (m, 14 H), 2.41 (s, 6 H), 2.67-3.04(m, 16 H), 3.50-3.57 (m, 8 H), 4.40-4.45 (m, 1H), 5.01-5.69 (m, 11 H),7.13-7.29 (m, 10 H) 9-48 0.69-0.93 (m, 26 H), 1.28-1.68 (m, 16 H), 2.16(s, 6 H), 2.66-3.04 (m, 16 H), 4.35-4.42 (m, 1 H), 4.9-5.68 (m, 11 H),6.05 (s, 2 H), 6.94-6.95 (m, 6 H), 7.31- 7.32 (m, 4 H) 9-49 0.60-0.89(m, 26 H), 1.01-1.77 (m, 16 H), 2.65-3.01 (m, 16 H), 4.35-4.45 (m, 1 H),5.05-5.67 (m, 11 H), 7.15-7.24 (m, 10 H), 8.18 (d, J = 2.4 Hz, 2H), 8.26(d, J = 8.0 Hz, 2H), 8.56 (d, J = 4.3 Hz, 2H) 9-50 0.68-0.95 (m, 26 H),1.12-1.75 (m, 22 H), 2.67-3.08 (m, 20 H), 4.39-5.71 (m, 12 H), 7.13 (d,4 H), 7.28-7.32 (m, 4 H), 7.91-7.93 (m, 2 H) 9-51 0.70-0.94 (m, 26 H),1.21-1.75 (m, 34 H), 2.67-3.08 (m, 16 H), 4.39-5.69 (m, 12 H), 7.03 (d,4 H), 7.27-7.31 (m, 4 H), 7.86-7.88 (m, 2 H) 9-52 0.68-0.94 (m, 26 H),1.20-1.90 (m, 32 H), 2.67-3.07 (m, 16 H), 3.28-3.36 (m, 2 H), 4.39-5.70(m, 12 H), 7.13 (d, 4 H), 7.28-7.32 (m, 4 H), 7.87-7.89 (m, 2 H) 9-530.68-0.95 (m, 38 H), 1.20-1.75 (m, 16 H), 1.95-2.04 (m, 2 H), 2.63-3.08(m, 20 H), 4.39-5.70 (m, 12 H), 7.14 (d, 4 H), 7.28-7.31 (m, 4 H), 7.95(s, 2 H) 9-54 0.68-0.94 (m, 26 H), 1.19-2.02 (m, 20 H), 2.16-2.26 (m, 8H), 2.66-3.07 (m, 16 H), 3.71-3.80 (m, 2 H), 4.39-5.70 (m, 12 H), 7.10(d, 4 H), 7.29 (d, 4 H), 7.92-7.94 (m, 2 H) 9-55 0.12-0.17 (m, 4 H),0.38-44 (m, 4 H), 0.68-1.04 (m, 28 H), 1.20-1.75 (m, 16 H), 2.66-3.07(m, 20 H), 4.39-5.70 (m, 12 H), 7.13 (d, 4 H), 7.29 (d, 4 H), 7.91 (s, 2H) 9-56 0.69-1.02 (m, 44 H), 1.20-1.75 (m, 16 H), 2.67-3.07 (m, 20 H),4.39-5.70 (m, 12 H), 7.15 (d, 4 H), 7.29 (d, 4 H), 7.90-7.92 (m, 2 H)9-57 0.68-1.05 (m, 34 H), 1.20-1.76 (m, 16 H), 2.15-2.25 (m, 8 H),2.68-3.08 (m, 16 H), 4.39-5.72 (m, 12 H), 7.19 (d, 4 H), 7.31 (d, 4 H)9-58 0.64-0.93 (m, 26 H), 1.16-1.72 (m, 16 H), 2.67-3.07 (m, 16 H),4.38-5.70 (m, 12 H), 7.02 (d, 4 H), 7.27 (d, 4 H), 7.58 (d, 4 H), 7.68(d, 4 H), 8.12 (s, 2 H) 9-59 0.68-0.95 (m, 26 H), 1.13-1.75 (m, 22 H),2.24 (s, 6 H), 2.67-3.08 (m, 20 H), 4.39- 5.71 (m, 12 H), 7.17 (d, 4 H),7.31 (d, 4 H) 9-60 0.71-0.92 (m, 23 H), 1.23-1.68 (m, 19 H), 2.67-3.06(m, 16 H), 3.40-3.50 (m, 4 H), 4.33-4.61 (m, 5 H), 5.01-5.84 (m, 11 H),6.72-6.89 (m, 2 H), 7.24-7.43 (m, 11 H), 7.91-7.93 (m, 1 H) 9-610.62-0.90 (m, 23 H), 1.23-1.83 (m, 19 H), 2.65-3.18 (m, 16 H), 3.69 (s,4 H), 4.30-4.50 (m, 1 H), 5.01-5.84 (m, 11 H), 7.01-7.17 (m, 10 H),8.15-8.17 (m, 2 H), 8.17-8.18 (m, 2 H) 9-62 0.70-0.94 (m, 24 H),1.20-1.90 (m, 18 H), 2.67-3.03 (m, 16 H), 3.60 (bs, 4 H), 3.97 (bs, 4H), 4.35-4.45 (m, 1 H), 4.66 (bs, 4 H), 5.03-5.68 (m, 7 H), 6.71- 6.77(m, 4 H), 7.21-7.28 (m, 10 H), 7.59-7.61 (m, 2 H) 9-63 0.72-0.98 (m, 26H), 1.24-1.75 (m, 16 H), 2.67-3.20 (m, 16 H), 3.34-3.42 (m, 4 H),4.36-4.48 (m, 4 H), 5.06-5.85 (m, 12 H), 7.15-7.60 (m, 10 H), 8.10-8.30(m, 4 H) 9-64 0.65-0.98 (m, 27 H), 1.20-1.80 (m, 15 H), 2.65-3.10 (m, 18H), 3.40-3.56 (m, 2 H), 3.80-3.88 (m, 2 H), 4.10-4.23 (m, 2 H),4.40-4.43 (m, 1 H), 4.76 (bs, 2 H), 4.99-5.78 (m, 9 H), 6.18-6.22 (m, 1H), 6.47-6.52 (m, 1 H), 6.85-6.95 (m, 2 H), 7.20-7.36 (m, 8 H),7.58-7.65 (m, 2H) 9-65 0.68-1.09 (m, 26 H), 1.20-1.80 (m, 16 H),2.60-3.15 (m, 16 H), 3.18-3.26 (m, 4 H), 3.54-3.59 (m, 4 H), 4.34-4.42(m, 1 H), 5.00-5.74 (m, 11 H), 7.15-7.80 (m, 12 H), 8.32-8.41 (m, 2 H)9-66 0.70-0.94 (m, 26 H), 1.23-1.70 (m, 16 H), 2.73-3.02 (m, 22 H), 3.22(bs, 4 H), 3.43-3.44 (m, 4H), 4.42-4.44 (m, 5 H), 5.01-5.69 (m, 7 H),6.30-6.32 (m, 2 H), 6.41-6.50 (m, 6 H), 7.18-7.20 (m, 4 H), 7.24-7.26(m, 4 H) 9-67 0.70-0.94 (m, 26 H), 1.23-1.69 (m, 34 H), 2.67-3.02 (m, 16H), 3.40 (bs, 4H), 3.72 (bs, 4 H), 4.39-4.42 (m, 1 H), 4.50 (s, 4 H),5.01-5.70 (m, 7 H), 6.51-6.57 (m, 4 H), 6.80 (t, J = 7.7 Hz, 2 H), 7.17(d, J = 7.9 Hz, 4 H), 7.26 (d, J = 7.8 Hz, 4 H), 7.32 (d, J = 8.0 Hz, 2H) 9-68 0.64-0.95 (m, 26 H), 1.23-1.69 (m, 16 H), 2.67-3.08 (m, 20 H),3.64-3.67 (m, 4 H), 4.35-4.55 (m, 5 H), 5.0-5.7 (m, 7 H), 6.49-6.53 (m,4 H), 6.81 (t, J = 7.8 Hz, 2 H), 6.94 (d, J = 7.5 Hz, 2 H), 7.18 (d, J =7.9 Hz, 4 H), 7.27 (d, J = 7.9 Hz, 4 H) 9-69 0.72-0.93 (m, 26 H),1.24-1.70 (m, 17 H), 2.67-3.03 (m, 16 H), 3.48-3.52 (m, 8 H), 4.35-4.45(m, 1 H), 4.50 (bs, 4 H), 5.02-5.68 (m, 8 H), 6.62 (bs, 4 H), 6.92- 7.26(m, 12 H)

The following Formula (1F2) compounds (hybrid analogs) described inTable 10 were prepared in accordance with the schemes and examplesdescribed herein. Ring B is as described herein.

TABLE 10 Formula (1F2) Compounds Ex. # Ring B 10-1 

10-2 

10-3 

10-4 

10-5 

10-6 

10-7 

10-8 

10-9 

10-10

10-11 No Example 10-12

10-13

10-14

10-15

10-16

10-17

10-18

10-19

10-20

10-21

10-22

10-23

10-24

10-25

10-26

10-27

10-28

10-29

10-30

10-31

10-32

10-33

10-34

10-35

10-36

10-37

10-38

10-39

10-40

10-41

The following Formula (1F2) compound names and example #'s refer tothose compounds depicted in Table 10. In one aspect of the invention,are Formula (1F2) compounds selected from:

-   (10-1).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-(thiomorpholinomethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1064);-   (10-2).    (3S,6R,9S,12R,15S,18S,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-(piperidin-1-ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1046);-   (10-3).    (3S,6R,9S,12R,15S,18S,21S,24R)-6-benzyl-18-(4-((4,4-difluoropiperidin-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1082);-   (10-4).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-[[4-(1,2,4-triazol-1-ylmethyl)phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1032);-   (10-5).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((1-oxidothiomorpholino)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1080);-   (10-6).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-(morpholinomethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1048);-   (10-7).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)piperidine-4-carbonitrile    (1071);-   (10-8).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-18-(4-((4-methoxypiperidin-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1076);-   (10-9). tert-butyl    4-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)piperazine-1-carboxylate    (1147);-   (10-10).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1195);-   (10-11). No Example; (10-12).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((2-oxoquinolin-1(2H)-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1106);-   (10-13).    1-[[4-[[(2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracos-2-yl]methyl]phenyl]methyl]pyrrole-2-carbonitrile    (1054);-   (10-14).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1079);-   (10-15).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1079);-   (10-16).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1096);-   (10-17).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1056);-   (10-18).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((2-oxooxazolidin-3-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1048);-   (10-19).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1060);-   (10-20).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((4-((3-chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1171);-   (10-21).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-((p-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1150);-   (10-22).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-18-(4-((4-((4-methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1166);-   (10-23).    3-((1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzonitrile    (1161);-   (10-24).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((5-(hydroxymethyl)-2-oxooxazolidin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1078);-   (10-25).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((2-oxo-1,3-oxazinan-3-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1062);-   (10-26).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-indazol-1-yl)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1079);-   (10-27).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1070);-   (10-28).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((6,7-dihydropyrano[4,3-c]pyrazol-2(4H)-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1085);-   (10-29).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((7H-purin-7-yl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1081);-   (10-30).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-5-methyl-1H-pyrrole-2-carbonitrile    (1067);-   (10-31).    1-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrrole-2,5-dicarbonitrile    (1078);-   (10-32).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1084);-   (10-33).    (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1,1-dioxido-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1143);-   (10-34).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-(2,3-dihydropyrido[4,3-b][1,4]oxazin-4-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1098);-   (10-35).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-(2,3-dihydropyrido[2,3-b][1,4]thiazin-1-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1111);-   (10-36).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone,    hydrochloride (1094);-   (10-37).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-(2,3-dihydropyrido[3,2-b][1,4]oxazin-4-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1096);-   (10-38).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-[[4-(2,3-dihydropyrido[2,3-b][1,4]oxazin-1-ylmethyl)phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone    (1096);-   (10-39).    tert-butyl4-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate    (1194);-   (10-40).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1108); and-   (10-41).    (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone    (1111).

TABLE 10′ Formula (1F2) Table 10 Compound NMRs (1H NMR (400 Mhz,DMSO-d₆) δ ppm) Example NMR 10-1  1H NMR (400 MHz, CDCl3) δ 0.70-1.05(m, 30 H), 1.30-1.80 (m, 12H), 2.60-3.20 (m, 24H), 3.46 (bs, 2H),4.40-4.50 (m, 1H), 5.00-5.70 (m, 7H), 7.15-7.32 (m, 9H) 10-4  0.67-0.96(m, 26H), 1.17-1.74 (m, 16 H), 2.67-3.11 (m, 16 H), 4.39-5.74 (m, 10 H),7.20-7.37 (m, 9H), 8.82-8.86 (m, 2H) 10-6  0.72-1.11 (m, 26H), 1.16-1.76(m, 16H), 2.27-2.43 (m, 4H), 2.48-3.15 (m, 16 H), 3.33-3.46 (m, 2H),3.55-3.68 (m, 4H), 3.95-5.94 (m, 8 H), 7.06-7.35 (m, 9H) 10-9  0.57-1.04(m, 26 H) 1.08-1.92 (m, 26 H) 2.56-3.21 (m, 17 H) 3.28 (br s, 2 H) 4.02(br s, 2 H) 4.23-4.47 (m, 3 H) 4.93-5.85 (m, 8 H) 7.12-7.55 (m, 9 H)10-10 0.57-1.09 (m, 26 H) 1.09-1.85 (m, 16 H) 2.59-3.24 (m, 20 H)3.24-3.93 (m, 6 H) 4.18-4.54 (m, 3 H) 4.98-5.86 (m, 8 H) 7.17-7.63 (m, 9H) 10-11 0.58-1.06 (m, 26 H) 1.14-1.85 (m, 16 H) 2.62-3.40 (m, 22 H)4.42 (m, 1 H) 4.60 (s, 4 H) 4.85-5.91 (m, 8 H) 7.12-7.58 (m, 9 H) 10-120.51-1.02 (m, 26 H) 1.08-1.82 (m, 16 H) 2.60-3.14 (m, 16 H) 4.31-4.48(m, 1 H) 4.96-5.81 (m, 9 H) 6.73-6.87 (m, 1 H) 7.08-7.18 (m, 2 H)7.20-7.41 (m, 9 H) 7.45-7.56 (m, 1 H) 7.84-7.90 (m, 1 H) 7.92-8.01 (m, 1H) 10-13 0.63-1.03 (m, 26 H), 1.16-1.79 (m, 16 H), 2.64-2.97 (m, 13 H),2.99-3.13 (m, 3 H), 4.36-4.49 (m, 1 H), 4.98-5.78 (m, 11 H), 6.17-6.29(m, 1 H), 6.95 (d, J = 3.42 Hz, 1 H), 7.12 (m, 2 H), 7.21-7.39 (m, 8 H)10-14 0.60-1.00 (m, 27 H) 1.05-1.82 (m, 15 H) 2.57-3.14 (m, 16 H)4.34-4.45 (m, 1 H) 4.95-5.79 (m, 8 H) 5.84-6.05 (m, 2 H) 6.99-7.10 (m, 1H) 7.19-7.54 (m, 9 H) 7.62-7.75 (m, 1 H) 7.99 (br s, 1 H) 8.70-8.83 (m,2 H) 13.48-13.63 (m, 1 H) 10-15 0.57-1.04 (m, 27 H) 1.07-1.84 (m, 15 H)2.60-3.14 (m, 16 H) 4.35-4.49 (m, 1 H) 5.64 (s, 10 H) 6.87-6.99 (m, 1 H)7.15-7.54 (m, 9 H) 8.09-8.22 (m, 1 H) 8.30- 8.39 (m, 1 H) 8.42-8.52 (m,1 H) 9.40-9.50 (m, 1 H) 12.98-13.12 (m, 1 H) 10-16 0.59-1.03 (m, 27 H),1.15-1.79 (m, 15 H), 2.63-3.15 (m, 16 H), 4.20 (br s, 2 H), 4.36-4.48(m, 3 H), 4.97-5.78 (m, 9 H), 6.46-6.54 (m, 1 H), 6.57-6.62 (m, 1 H),6.62-6.71 (m, 2 H), 7.16-7.40 (m, 9 H) 10-17 0.6-1.0 (m, 32H), 1.1-1.8(m, 20 H), 2.6-3.1 (m, 16 H), 4.3-4.5 (m, 0.85H), 5.0-5.75 (m, 11 H),6.1-6.2 (m, 1H), 6.3-6.4 (m, 1H), 7.2-7.3 (9H), 7.35-7.45 (m, 1H), 7.7-7.75 (m, 1H). 10-18 0.58-1.09 (m, 26 H) 1.12-1.90 (m, 16 H) 2.61-2.99(m, 12 H) 3.38 (m, 2 H) 4.15- 4.49 (m, 4 H) 4.96-5.83 (m, 8 H) 7.12-7.51(m, 9 H) 10-19 0.58-1.01 (m, 26 H) 1.15-1.78 (m, 16 H) 2.64-3.13 (m, 16H) 4.37-4.45 (m, 1 H) 4.46-4.52 (m, 2 H) 4.98-5.77 (m, 9 H) 7.20-7.37(m, 9 H) 7.92-7.98 (m, 1 H) 10-20 0.58-1.02 (m, 26 H) 1.13-1.79 (m, 16H) 2.63-3.16 (m, 16 H) 4.37-4.50 (m, 1 H) 4.96-5.79 (m, 11 H) 6.93-7.04(m, 2 H) 7.10-7.17 (m, 1 H) 7.21-7.39 (m, 9 H) 8.20-8.29 (m, 1 H) 10-210.62-0.99 (m, 26 H) 1.13-1.78 (m, 16 H) 2.22 (s, 3 H) 2.64-3.14 (m, 16H) 4.36- 4.48 (m, 1 H) 4.97-5.78 (m, 11 H) 6.84-6.94 (m, 2 H) 7.04-7.13(m, 2 H) 7.21- 7.38 (m, 9 H) 8.17-8.24 (m, 1 H) 10-22 0.59-0.98 (m, 26H) 1.06-1.82 (m, 16 H) 2.61-3.16 (m, 16 H) 3.64-3.72 (m, 3 H) 4.35-4.51(m, 1 H) 4.97-5.81 (m, 11 H) 6.76-6.90 (m, 2 H) 6.90-7.03 (m, 2 H)7.21-7.41 (m, 9 H) 8.14-8.31 (m, 1 H) 10-23 0.62-1.02 (m, 26 H)1.06-1.81 (m, 16 H) 2.62-3.15 (m, 16 H) 4.38-4.48 (m, 1 H) 4.97-5.82 (m,11 H) 7.18-7.59 (m, 13 H) 8.24-8.31 (m, 1 H) 10-24 0.61-1.04 (m, 26H),1.12-1.93 (m, 16H), 2.61-3.25 (m, 15H), 3.32-3.62 (m, 3H), 4.21-4.61 (m,4H), 4.93-5.82 (m, 8H), 7.10-7.40 (m, 9H) 10-25 0.63-1.02 (m, 24H),1.12-2.0 (m, 18H), 2.58-3.24 (m, 17H), 4.09-4.28 (m, 2H), 4.33-4.49 (m,2H), 4.93-5.83 (m, 10H), 7.12-7.49 (m, 9H) 10-26 0.66-0.97 (m, 26 H),1.15-1.76 (m, 16 H), 2.64-2.95 (m, 13 H), 2.98-3.13 (m, 3 H), 4.38-5.76(m, 10 H), 6.99-7.03 (m, 1 H), 7.18-7.33 (m, 10 H), 7.56 (d, 1 H), 7.68(d, 1 H), 8.43 (s, 1 H) 10-27 0.80-0.95 (m, 24 H), 1.09-1.71 (m, 18 H),2.68-3.06 (m, 16 H), 4.13-4.20 (m, 4 H), 4.40-4.42 (m, 1 H), 5.01-5.69(m, 10 H), 7.21-7.30 (m, 9 H), 9.92 (brs, 2 H) 10-28 0.58-1.03 (m, 24H),1.14-1.86 (m, 16H), 2.55-3.16 (m, 16H), 3.72-3.92 (m, 2H), 4.33-4.50 (m,1H), 4.50-4.64 (m, 2H), 4.91-5.85 (m, 9H), 6.98-7.63 (m, 10H) 10-290.51-1.00 (m, 26 H), 1.08-1.92 (m, 16 H), 2.58-3.22 (m, 16 H), 4.41 (m,1 H), 4.47-4.49 (m, 1 H), 4.91-5.96 (m, 10 H) 7.14-7.73 (m, 9 H), 9.16(s, 1 H), 9.68 (s, 1 H), 9.95 (s, 1 H) 10-30 0.68-0.95 (m, 26 H),1.23-1.7 (m, 16 H), 2.16 (s, 3 H), 2.66-3.31 (m, 16 H), 4.35-4.45 (m, 1H), 5.02-5.8 (m, 9 H), 6.05 (d, J = 3.9 Hz, 1 H), 6.91-6.95 (m, 2 H),7.23-7.31 (m, 8 H) 10-31 0.68-0.96 (m, 26 H), 1.23-1.58 (m, 16 H),2.66-3.06 (m, 16 H), 4.40-4.42 (m, 1 H), 5.01-5.75 (m, 9 H), 7.11 (d, J= 7.9 Hz, 2 H), 7.21-7.31 (m, 7 H), 7.36-7.40 (m, 2 H) 10-32 0.80-0.94(m, 26 H), 1.34-1.85 (m, 16 H), 2.41 (s, 3 H), 2.67-3.05 (m, 16 H),3.50-3.57 (m, 4 H), 4.40-4.42 (m, 1 H), 5.11-5.69 (m, 9 H), 7.13-7.31(m, 10 H) 10-33 0.70-0.94 (m, 24 H), 1.20-1.73 (m, 18 H), 2.67-3.05 (m,16 H), 3.60 (bs, 2 H), 3.97 (bs, 2 H), 4.35-4.45 (m, 1 H), 4.66 (bs, 2H), 5.03-5.78 (m, 7 H), 6.71-6.77 (m, 2 H), 7.21-7.30 (m, 10 H),7.59-7.61 (m, 1 H) 10-34 0.60-1.00 (m, 26 H), 1.15-1.80 (m, 16 H),2.65-3.10 (m, 16 H), 3.30-3.41 (m, 2 H), 4.38-4.42 (m, 2 H), 5.00-5.78(m, 10 H), 7.19-7.48 (m, 10 H), 8.14-8.30 (m, 2 H) 10-35 0.65-1.03 (m,27 H), 1.20-1.80 (m, 15 H), 2.65-3.15 (m, 16 H), 3.18-3.28 (m, 2 H),3.55-3.62 (m, 2 H), 4.39-4.46 (m, 1 H), 5.00-5.80 (m, 9 H), 7.20-7.80(m, 11 H), 8.35-8.40 (m, 1 H) 10-36 0.65-1.00 (m, 26 H), 1.11-1.76 (m,16 H), 2.65-3.10 (m, 16 H), 4.35-4.50 (m, 4 H), 5.00-5.80 (m, 11 H),6.50-6.90 (m, 4 H), 7.20-7.38 (m, 9 H) 10-37 0.70-0.94 (m, 26 H),1.27-1.68 (m, 16 H), 2.68-3.05 (m, 16 H), 4.15 (s, 2 H), 4.40-4.43 (m, 1H), 4.77-5.73 (m, 11 H), 6.50-6.52 (m, 1 H), 6.95 (d, J = 7.2 Hz, 1 H),7.19-7.31 (m, 9 H), 7.64-7.65 (m, 1 H) 10-38 0.68-0.95 (m, 26 H),1.23-1.69 (m, 16 H), 2.67-3.05 (m, 16 H), 3.31-3.37 (m, 2 H), 4.33-4.44(m, 5 H), 5.09-5.69 (m, 7 H), 6.71-6.74 (m, 1 H), 6.88-6.91 (m, 1 H),7.22-7.37 (m, 10 H) 10-39 0.70-0.94 (m, 26 H), 1.23-1.70 (m, 25 H),2.67-3.05 (m, 16 H), 3.40 (bs, 2 H), 4.42-4.50 (m, 3 H), 5.02-5.70 (m, 9H), 6.51-6.54 (m, 2 H), 6.80 (bs, 1 H), 7.16- 7.31 (m, 10 H) 10-400.84-0.94 (m, 26 H), 1.42-1.70 (m, 16 H), 2.67-2.95 (m, 16 H), 3.22 (s,3 H), 3.43-3.44 (2H, m), 4.39-4.43 (m, 3 H), 5.02-5.73 (m, 9 H),6.30-6.47 (m, 4 H), 7.18-7.31 (m, 9 H) 10-41 0.68-0.95 (m, 26 H),1.23-1.69 (m, 16 H), 2.67-3.09 (m, 18 H), 3.64-3.67 (m, 2 H), 4.4-4.55(m, 3 H), 5.0-5.75 (m, 7 H), 6.51-6.54 (m, 2 H), 6.81-6.82 (m, 1 H),6.93-6.95 (m, 1 H), 7.17-7.31 (m, 9 H)Biological

Heartworm infection, caused by the endoparasite Dirofilaria immitis (D.immitis), can be a severe and life-threatening disease in animals suchas dogs and cats. Heartworm has a complicated life cycle involvingseveral life stages before they mature into adults that will eventuallyinfect the pulmonary artery of the host animal. Heartworm transmissionalso requires the mosquito to act as an intermediate host to completethis life cycle. For example, the beginning of the heartworm life cycleand transmission process involves a mosquito biting a previouslyinfected dog and ingesting blood containing heartworm microfilariae(larva stage 1). Within the mosquito, the microfilariae will molt intoinfective larva stage 3 (L3) worms over a two week period. Once themosquito bites another dog, infective L3 worms will move through thebite wound to enter the host and migrate into the tissues where theywill begin molting into larva stage 4 (L4) worms, usually within 1 to 3days post infection. Subsequently, L4 worms will continue theirmigration through tissues and molt into sexually immature or“adolescent” adults (larva stage 5, immature adult), approximately 50-70days post infection. Sexually mature worms will eventually migrate tothe heart and lungs of the dog, as early as 70 days post infection.Approximately 6-7 months post infection D. immitis adults reach maturityand sexually reproduce in the pulmonary artery leading to microfilaria(MF) production and circulation in the blood of the dog, thus completingthe heartworm life cycle.

The most commonly used heartworm preventatives are the macrocycliclactones (MLs) such as ivermectin, moxidectin and selamectin. Theseagents are administered on a monthly basis whereby they kill D. immitisL3 and L4 worms acquired by the host within the previous 30 days. Theirprimary action is to disrupt the heartworm life cycle by killing L3 andL4 worms thus preventing adult formation and subsequent disease. Whilevery effective at preventing heartworm disease, owners are advised totest dogs for existing heartworm infections (i.e. heartworm positivedogs) prior to starting treatment with MLs due to their potential tokill circulating microfilariae. A rapid decrease in the numbers ofmicrofilariae in the blood can lead to hypersensitivity-type reactionsand circulatory shock (e.g. anaphylaxis), presumably due to dead ordying microfilariae. These potential adverse effects can belife-threatening to the dog and as such are presented as cautionstatements on many ML product labels. Therefore, the discovery of anovel heartworm preventative that would selectively target L3 and L4stage worms versus microfilariae would offer a potential safetyadvantage. By not killing circulating microfilariae in heartwormpositive dogs, a targeted treatment would prevent the adverse effectsknown to occur with other heartworm preventatives that lack D. immitisstage selectivity.

To identify novel heartworm preventatives, compounds were screened fornematocidal activity using in vitro motility assays. The compoundsdescribed herein have demonstrated nematocidal activity against eitherDirofilaria immitis (Larva stage 4 (DiL4)) and/or Dirofilaria immitis(microfilaria (D/MF)) as determined by reductions in nematode motilityeither by paralysis or death. Active and selective (DiL4 vs. DiMFpotency) example compounds were subsequently evaluated in heartwormpositive dog studies to correlate the in vitro selectivity profile within vivo effects on circulating microfilariae.

The in vitro (DiL4 and DiMF) and in vivo (heartworm positive dogstudies) biological activity against Dirofilaria immitis of thecompounds of the invention can be measured using the test methodsdescribed below.

Dirofilaria immitis, Microfilaria (D/MF) In Vitro Assay

Compounds were dissolved and serially diluted in DMSO. Aliquots werespotted to the empty wells of assay plates. Media and microfilariae ofDirofilaria immitis were added to each well to dilute the test compoundsto the desired concentrations. Assay plates were incubated forapproximately 72 hours, and the larvae in each well were observedmicroscopically for drug effect. Microfilariae in each well wereassessed subjectively for survival or paralysis, and results werereported as Minimum Effective Dose (MED). In accordance with the methoddescribed above, the following compounds had DiMF MED≤1 nM: 1a-36,1a-37, 1b-16, 1b-17, 1b-18, 1b-23, 1b-32, 1b-66, 1b-86, 1b-96, 1b-104,1b-115, 1b-146, 1b-160, 1b-166, 1b-168, 1b-171, 1b-173, 1b-176, 1b-177,1b-189, 1b-194, 1b-208, 1b-212, 1c-1, 1c-3, 1c-4, 1c-6, 1c-7, 1c-9,1c-10, 2-1, 2-30, 6-3, 6-9, 6-15, 8-9, 9-12, 9-16, 9-32, 9-50, 9-54,9-55, 10-13, and 10-31. The following compounds had DiMF MED>1 nM and≤10 nM: 1a-1, 1a-2, 1a-7, 1a-10, 1a-11, 1a-16, 1a-17, 1a-20, 1a-21,1a-24, 1a-38, 1a-46, 1b-7, 1b-8, 1b-10, 1b-19, 1b-21, 1b-24, 1b-25,1b-29, 1b-35, 1b-46, 1b-52, 1b-62, 1b-70, 1b-89, 1b-94, 1b-95, 1b-103,1b-105, 1b-108, 1b-118, 1b-119, 1b-121, 1b-126, 1b-135, 1b-142, 1b-143,1b-145, 1b-150, 1b-151, 1b-152, 1b-154, 1b-155, 1b-165, 1b-174, 1b-175,1b-184, 1b-190, 1b-197, 1b-201, 1b-203, 1b-205, 1b-207, 1b-211, 1b-213,1b-215, 1b-216, 1b-220, 1b-221, 1c-2, 1c-5, 1c-11, 1c-12, 2-2, 2-7,2-10, 2-12, 2-18, 2-19, 2-22, 2-25, 2-28, 2-29, 2-39, 2-41, 2-44, 2-45,2-46, 2-47, 2-48, 2-51, 2-55, 2-62, 2-65, 2-66, 2-69, 2-74, 2-75, 2-76,2-77, 2-87, 3-1, 3-2, 3-3, 3-8, 3-11, 3-27, 3-36, 3-37, 3-39, 3-41, 4-1,4-2, 4-14, 5-1, 5-2, 6-1, 6-12, 6-16, 6-19, 6-20, 7-3, 7-9, 8-3, 8-7,8-8, 8-12, 8-13, 8-15, 9-1, 9-6, 9-11, 9-21, 9-22, 9-25, 9-28, 9-30,9-34, 9-41, 9-48, 9-49, 9-51, 9-52, 9-53, 9-56, 10-6, 10-17, 10-30,10-37, and 10-38. The following compounds had DiMF MED>10 and ≤100 nM:1a-3, 1a-6, 1a-8, 1a-12, 1a-13, 1a-14, 1a-15, 1a-18, 1a-19, 1a-22,1a-23, 1a-25, 1a-26, 1a-28, 1a-29, 1a-30, 1a-31, 1a-32, 1a-33, 1a-35,1a-39, 1b-4, 1b-5, 1b-12, 1b-13, 1b-15, 1b-20, 1b-22, 1b-31, 1b-34,1b-38, 1b-39, 1b-43, 1b-45, 1b-53, 1b-54, 1b-58, 1b-63, 1b-64, 1b-67,1b-69, 1b-71, 1b-75, 1b-87, 1b-91, 1b-97, 1b-106, 1b-110, 1b-111,1b-112, 1b-113, 1b-116, 1b-117, 1b-120, 1b-124, 1b-127, 1b-128, 1b-129,1b-133, 1b-138, 1b-139, 1b-140, 1b-141, 1b-144, 1b-149,1b-156,1b-159,1b-162, 1b-163, 1b-169, 1b-170, 1b-172, 1b-180, 1b-181,1b-183,1b-185, 1b-186,1b-187, 1b-188, 1b-191, 1b-195, 1b-198, 1b-199,1b-206, 1b-209, 1b-210, 1b-214, 1b-217, 1b-218, 1b-219, 1b-222, 2-3,2-5, 2-8, 2-9, 2-11, 2-13, 2-14, 2-15, 2-16, 2-17, 2-20, 2-21, 2-23,2-24, 2-26, 2-27, 2-31, 2-32, 2-35, 2-36, 2-38, 2-40, 2-42, 2-43, 2-50,2-52, 2-54, 2-56, 2-57, 2-58, 2-59, 2-60, 2-61, 2-64, 2-67, 2-68, 2-70,2-71, 2-72, 2-78, 2-79, 2-81, 2-82, 2-83, 2-84, 2-85, 2-86, 2-88, 3-10,3-12, 3-13, 3-18, 3-19, 3-20, 3-21, 3-23, 3-24, 3-25, 3-29, 3-38, 3-43,4-9, 4-15, 4-16, 4-17, 5-3, 5-4, 5-6, 6-2, 6-4, 6-5, 6-6, 6-7, 6-8,6-10, 6-11, 6-14, 6-18, 7-1, 7-2, 7-4, 7-7, 7-11, 8-2, 8-4, 8-5, 8-6,8-10, 8-11, 8-14, 9-2, 9-4, 9-5, 9-18, 9-20, 9-27, 9-29, 9-33, 9-35,9-42, 9-57, 9-58, 9-59, 9-61, 9-62, 9-64, 10-2, 10-3, 10-9, 10-10,10-11, 10-12, 10-14, 10-16, 10-18, 10-19, 10-21, 10-22, 10-23, 10-24,10-25, 10-26, 10-27, 10-28, 10-32, 10-33, 10-35, and 10-41.

Dirofilaria immitis, L4 Stage (D/L4) In Vitro Assay

Compounds were dissolved and serially diluted in DMSO. Aliquots werespotted to the empty wells of assay plates. Media and 4th stage larvae(L4) of Dirofilaria immitis were added to each well to dilute the testcompounds to the desired concentrations. Assay plates were incubated forapproximately 72 hours, and the larvae in each well were observedmicroscopically for drug effect. Larvae in each well were assessedsubjectively for survival or paralysis, and results were reported asMinimum Effective Dose (MED)). In accordance with the method describedabove, the following compounds had DiL4 MED 0.1 nM: 1a-7, 1b-15, 1b-66,1b-89, 1b-96, 1b-115, 1b-119, 1b-154, 1b-166, 1b-171, 1b-176, 1b-177,1b-211, 1b-216, 1c-1, 1c-2, 1c-3, 1c-6, 1c-7, 1c-8, 1c-10, 1c-11, 6-3,6-9, 6-12, 9-12, 9-16, 9-48, and 10-31. The following compounds had DiL4MED>0.1 and ≤1 nM: 1a-1, 1a-11, 1a-12, 1a-13, 1a-16, 1a-20, 1a-21,1a-26, 1a-31, 1a-36, 1a-37, 1b-16, 1b-17, 1b-21, 1b-23, 1b-25, 1b-32,1b-35, 1b-46, 1b-51, 1b-86, 1b-104, 1b-108, 1b-112, 1b-113, 1b-118,1b-126, 1b-129, 1b-150, 1b-151, 1b-160, 1b-165, 1b-173, 1b-186, 1b-189,1b-190, 1b-194, 1b-205, 1b-206, 1b-209, 1b-210, 1b-212, 1b-215, 1b-217,1b-219, 1b-222, 1c-4, 1c-5, 1c-12, 1c-13, 2-1, 2-10, 2-22, 2-25, 2-28,2-41, 2-51, 2-55, 2-62, 2-64, 2-66, 2-69, 2-76, 2-77, 3-1, 3-3, 3-18,3-19, 3-27, 3-36, 3-37, 4-2, 6-15, 7-3, 7-9, 8-3, 8-9, 8-12, 8-15, 9-25,9-26, 9-32, 9-55, 10-13, 10-30, and 10-38. The following compounds hadDiL4 MED>1 to ≤10 nM: 1a-34, 1a-38, 1a-39, 1b-14, 1b-19, 1b-68,

As a means of assessing the compounds selectivity against D. immitismicrofilaria and L4 larvae, selectivity was calculated as a ratio(DiMF/DiL4). The following compounds had a DiMF/DiL4 ratio≥10 and<100:1a-1, 1a-12, 1a-13, 1a-20, 1a-26, 1a-31, 1a-34, 1b-14, 1b-35,1b-46, 1b-69, 1b-89, 1b-96, 1b-108, 1b-113, 1b-126, 1b-127, 1b-128,1b-129, 1b-149, 1b-151, 1b-171, 1b-172, 1b-186, 1b-206, 1b-209, 1b-215,1b-216, 1b-217, 1b-219, 1c-5, 1c-8, 1c-10, 1c-11, 2-41, 2-55, 2-69, 3-3,3-18, 3-19, 4-2, 6-12, 9-16, 9-61, 10-31, and 10-38. The followingcompounds had a DiMF/DiL4 ratio 100:1a-7, 1b-15, 1b-51, 1b-68, 1b-112,1b-119, 1b-153, 1b-154, 1b-178, 1b-210, 1b-222, 1c-2, 1c-3, 1c-11,1c-13, 2-64, 9-26, 9-48, and 9-63.

Heartworm Positive Dog Studies

Dogs with pre-existing heartworm infections, via surgicaltransplantation were used for these studies. To confirm that the dogshad circulating microfilariae, blood samples were taken from each dogand examined for microfilariae by using the modified Knott's method. Alldog cohorts included in the studies exhibited average microfilariaecounts of at least 15,000 MF/mL of the blood (pre-dose). Onapproximately Day −7, dogs were randomly allocated to treatments (threeanimals per treatment group) based on Day −7 MF counts. Dogs were fastedovernight prior to dosing and fed immediately following dosing of thetest articles. Compounds were administered by point dosing in oralliquid-filled capsules on Day 0. Blood samples were collected to measureMF counts on Days 0 (pre-dose and 2 hours post-dose), 1, 2, 7, 21 and28. Clinical observations were conducted by a suitably experiencedveterinarian on days −7, 0 (immediately prior to treatment, 1-2 hourspost-treatment), 1 and 2 whereby any abnormal clinical signs weredocumented using standard veterinary medical terminology. Additionally,general health observations were conducted throughout the studyincluding (but not limited to) general physical appearance and behavior,abnormalities of food and water consumption, vomiting/regurgitation,appearance of urine and feces and any sign of MF anaphylaxis.

The reference depsipeptide, emodepside, has equivalent in vitro potencyagainst DiL4 (30 nM) and DiMF (30 nM) when assessed in the nematodemotility assays and therefore represents a non-selective compound, i.e.,selectivity ratio (DiMF/D/L4) of 1. Data from this comparison is shownin Table 11. As such, emodepside was evaluated for effects againstcirculating microfilariae in a heartworm positive dog study. At a doseof 1 mg/kg (po), emodepside demonstrated a rapid killing of circulatingmicrofilariae, reducing the average MF counts from 61,000 MF/mL of bloodpre-dose to 8,300 MF/mL of blood at 2 hours post-dose (˜86% decrease).Moreover, all treated dogs exhibited adverse effects consistent withdead or dying circulating microfilariae (e.g. lethargy, tremors, ataxia,hyper-salivation) within 2 hours of emodepside administration. All dogswere treated with dexamethasone, epinephrine and valium such that theywere able to recover from their symptoms.

In contrast to emodepside, the compounds described herein demonstratelarva stage selectivity (i.e. DiL4 vs. DiMF potency). As such, twocompound examples were progressed into heartworm positive dog studies tocorrelate the in vitro selectivity profile with in vivo effects oncirculating microfilariae. The DiL4 and DiMF MED for Example 1b-14 was 6nM and 300 nM, respectively. For Example 1b-25, the DiL4 and DiMF MEDwas 0.6 nM and 5 nM, respectively. Example 1b-25, which has aselectivity ratio of about 8.3, was dosed up to 3 mg/kg (po) with nosignificant effects on circulating MF counts out to day 21 post-dose.Additionally, there were no adverse effects observed following theadministration of Example 1b-25, consistent with a lack of microfilariaekill in the blood. Similarly, Example 1b-14, which exhibits aselectivity ratio of 50, was dosed at 1 mg/kg (po) with no significanteffects on circulating MF counts throughout the dog study. Average meanMF counts were 15,000 MF/mL of blood pre-dose and remained elevatedthroughout the study where it averaged 28,000 MF/mL of blood on day 21of the dog study. Moreover, there were no adverse clinical observationsnoted throughout the study, consistent with a lack of potency againstcirculating MF in the dogs. These data highlight the importance ofgenerating larva stage selective compounds as novel heartwormpreventatives. Specifically targeting the L4 stage versus the MF stageworms provide an improved safety profile when administeringpreventatives to dogs with an already active adult heartworm infection.Indeed, the compounds described herein exhibit improved selectivityratios (i.e. DiL4 vs. DiMF potency) whereby they offer improved safetyover older preventatives and reference depsipeptides such as emodepside.

TABLE 11 Heartworm positive dog studies evaluating effects oncirculating microfilariae (MF) following compound administration. Day 0,Day 0 Post-dose, Compound Pre-dose 2 hours Day 1 Day 7 Day 14 Day 21Emodepside Mean MF/mL 61,000  8,300  4,500  8,800 13,000 13,000 %Reduction 86% 93% 86%  79%  79% Example Mean MF/mL 15,000 20,000 14,00015,000 33,000 28,000 1b-14 % Reduction −33%   7%  0% −120% −87% ExampleMean MF/mL 32,000 34,000 26,000 27,000 40,000 46,000 1b-25 % Reduction−6% 19% 16%  −25% −44% Microfilariae raw counts are shown as mean MF/mL(3 dogs/treatment) of blood. Percent reductions were calculated fromcounts on day of assessment compared back with pre-dose (Day 0) levels.Negative percent reductions are a reflection of natural variabilityacross time due to active adult heartworm infection and continuedmicrofilariae production.

Canine pharmacokinetic (PK) data is provided for some Formula (1)compounds that were administered orally or intravenously in Table 12. Ascan be seen, the compounds have long plasma half-lives and clearancevalues that are low or moderate. The oral bioavailability is variableranging from a low of less than 1% to well absorbed at 78%.

TABLE 12 Pharmacokinetic Data from Dogs Following a Single IV or OralDose Dose of a Formula (1) compound Oral 1 mg/kg IV 0.5 or 0.2 mg/kgCmax F t½ Cl Vdss Example # (ng/mL) (%) (hrs) (mL/min/kg) (mL/kg) 1b-14111 10 138 0.9 2700 1b-15 5 0.2  67 0.05 320 1b-19 267 24  87 2.4 72501b-21 145 78   36.1 15.5 28400 1b-23 205 34  27 14 8540 1b-25 152 12 1102 3000 1b-45 127  104* 1b-68 39 4 163 1 7580 1b-69 27 5 256 1 3810 1b-108 178 30  51 6 5600  9-26 71 1 106 0.1 600 *oral t½Haemonchus contortus L3 (HcL3) Assay

Compounds were dissolved and serially diluted in DMSO. Aliquots werespotted to the empty wells of assay plates. Media and third stage larvaeof Haemonchus contortus were added to each well to dilute the testcompounds to the desired concentrations. Assay plates were incubated forapproximately 96 hours, and the larvae in each well were observedmicroscopically for drug effect. Larvae in each well were assessedsubjectively for survival or paralysis, and results were reported asMinimum Effective Dose (MED). In accordance with the method describedabove, the following compounds had an MED≤1 μM: 1b-18, 1b-23, 1b-66,1b-89, 1b-94, 1b-96, 1b-104, 1b-108, 1b-115, 1b-151, 1b-160, 1b-165,1b-171, 1b-173, 1b-176, 1b-177, 1b-206, 1b-211, 1b-212, 1b-215, 1b-216,1b-217, 1b-219, 1b-222, 1c-1, 1c-2, 1c-3, 1c-4, 1c-5, 1c-6, 1c-7, 1c-9,1c-10, 1c-11, 9-12, 9-16, 9-32, 9-48, and 9-55. The following compoundshad an MED>1 and ≤10 μM: 1a-10, 1a-14, 1a-16, 1a-17, 1a-20, 1a-21,1a-26, 1a-31, 1a-35, 1a-36, 1a-37, 1b-16, 1b-17, 1b-19, 1b-21, 1b-24,1b-29, 1b-46, 1b-52, 1b-95, 1b-110, 1b-118, 1b-126, 1b-127, 1b-129,1b-143, 1b-145, 1b-166, 1b-179, 1b-186, 1b-187, 1b-190, 1b-197, 1b-201,1b-207, 1b-210, 1b-213, 1b-214, 1b-221, 2-1, 2-2, 2-7, 2-19, 2-22, 2-28,2-30, 2-45, 2-51, 2-53, 2-66, 2-68, 2-69, 2-74, 2-79, 2-87, 3-1, 3-2,3-3, 3-27, 6-3, 6-7, 6-9, 6-12, 6-20, 7-9, 8-3, 8-4, 8-6, 8-7, 8-8, 8-9,8-13, 8-15, 9-1, 9-6, 9-11, 9-22, 9-28, 9-34, 9-41, 9-50, 9-51, 9-52,9-53, 9-54, 9-56, 9-57, 9-59, 10-3, 10-6, 10-11, 10-13, 10-17, 10-18,10-30, and 10-31. The following compounds had an MED>10 and ≤100 μM:1b-25, 1b-32, 1b-35, 1b-86, 1b-119, 1b-189, 1b-203, 1b-208, 1b-220, and9-69.

We claim:
 1. A compound of Formula (1A1-1)

stereoisomers thereof, and veterinary acceptable salts thereof; whereineach pyrazole is independently and separately optionally substitutedwith at least one to three substituents selected from the groupconsisting of C₁-C₆alkyl, halo, cyano, hydroxy, C₁-C₆haloalkyl,C₃-C₆cycloalkyl optionally substituted with at least one substituentselected from fluoro, chloro, methyl and methoxy; C₁-C₆alkoxy; phenyloptionally substituted with at least one substituent selected from haloand methoxy; —C₁-cyclopropyl; pyrimidinyl; pyrazinyl; pyridinyloptionally substituted with F and methyl; —CH₂OCH₃; —CH₂OCH₂CH₃;—OCH₂-cyclopropyl; and C₂-C₆alkynl optionally substituted withcyclopropyl or phenyl; selected from the group consisting of:(3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(4-((3-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(4-hydroxy-3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-hydroxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-(pyrazol-1-ylmethyl)phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(4-ethynyl-1H-pyrazol-1yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-3,5-dicarbonitrile);(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(cyclopropylmethoxy)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxy-5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(ethoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(6-methylpyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(5-methyl-1H-pyrazole-3-carbonitrile);(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;and(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(1-methoxyethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone.2. A composition comprising a compound of claim 1, stereoisomer thereof,or a veterinary acceptable salt thereof, and further comprising aveterinary acceptable excipient.
 3. The composition of claim 2, furthercomprising at least one additional antiparasitic agent.
 4. A method oftreating a parasitic infection in an animal in need thereof byadministering an effective amount of a compound of claim 2 stereoisomerthereof, and veterinary acceptable salt thereof, to said animal.
 5. Themethod of claim 4 wherein the effective amount of the compound isadministered to the animal in need thereof by oral, injectable, ortopical administration.
 6. The method of claim 4 wherein the parasiticinfection is an endoparasitic infection.
 7. The method of claim 6wherein the endoparasitic infection is caused by a filarial parasite. 8.The method of claim 7 wherein the filarial parasite is a Dirofilariaparasite and the animal is a companion animal.
 9. The composition ofclaim 3, wherein the at least one additional antiparasitic agent isselected from the group consisting of moxidectin, doramectin,selamectin, abamectin, milbemycin, milbemycin oxime, pyrantel,praziquantel, and levamisole.
 10. The method of claim 8, wherein thecompanion animal is canine.